Carbohydrate Chemistry Volume 34
A Specialist Periodical Report
Carbohydrate Chemistry
Monosaccharides, Disaccharides and Specific Oligosaccharides Volume 34 A Review of the Literature Published during 2000
Senior Reporter R.J. Ferrier, Industrial Research Limited, Lower Huit, New Zealand Reporters P. Benjes, Industrial Research Limited, Lower Hutt, New Zealand R. Blattner, Industrial Research Limited, Lower Hutt, New Zealand R.A. Field, University of St. Andrews, St. Andrews, UK R.H. Furneaux, Industrial Research Limited, Lower Hutt, New Zealand C. Hamilton, University of East Anglia, Norwich, UK J.O. Hoberg, Victoria University of Wellington, Wellington, New Zealand K.P.R. Kartha, University of St. Andrews, St. Andrews, UK P.C. Tyler, Industrial Research Limited, Lower Hutt, New Zealand R.H. Wightman, Heriot-Watt University, Edinburgh, UK
RSaC
advancing the chemical sciences
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ISBN 0-85404-238-5
ISSN 095 1-8428
A catalogue record for this book is available from the British Library 0 The Royal Society of Chemistry 2003
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In order to address the ever-increasing significance of carbohydrates in biology the presentation of material in this volume has been somewhat modified. A new introductory chapter (1)highlights some of the reviews published during the year that give an overview of the glycobiological aspects of carbohydrate chemistry, and another new chapter (20) brings together reports of the use of enzymic methods in the field - particularly those employed in the synthesis of glycosides and especially di- and oligosaccharides. There is consequently some inevitable overlap between Chapter 20 and Chapters 3 and 4. Antibiotics no longer have their separate chapter, rather material on this topic is distributed between the chapters on e.g. glycosides and nucleosides. The various analytical and separatory methods, which in previous volumes had their own chapters, are now covered together in Chapter 21. As was foreshadowed in the Preface to Volume 33 the present team completes its writing responsibilities with Volume 34, the decision having been forced by the ever-increasing workload involved in covering not just an expanding field but one of appreciably greater complexity. While it used to be a relatively straightforward task to abstract a paper and assign the prkcis to one of the chapters, it is now commonplace to find important features of a report which fall under several headings. All too often, it has appeared to the writers, important material was being buried in the mass, and highly significant and long papers have had to be condensed beyond an appropriate degree. Our procedures do not allow automatic searching, and in the face of powerful alternatives, it has to be conceded that this is a fundamental weakness. It also has to be accepted that, despite much effort to reduce the delay in publication, we have not achieved our objectives. Nevertheless, the approach adopted over 34 years has provided a search method with unique advantages, bringing together related chemistry in a way that facilitates searching within categories of particular compounds and which affords a ‘snapshot’ of the state of each category at a particular point in time. Highlights this year are the major syntheses of everninomycin and of glycoconjugate-based anti-cancer antigens mentioned at the beginning of Chapter 4, and also the less spectacular but highly significant developments in the vital area of synthesis of oligosaccharides. The further recognition of the desirability of using complementary and tuned donors and acceptors, the advances in ‘one-pot’, biochemical and automated procedures indicate very real progress, but nevertheless, each oligosaccharide still appears to presents its own challenges.
vi
Preface
This year Paul Benjes and Chris Hamilton contributed to the abstracting and writing tasks. Their help has been much appreciated, and their longer serving colleagues are thanked warmly for all their efforts over, in some cases, many years. Richard Wightman has been a particular tower of strength during the production of 17 volumes, always providing many of the most complex and detailed abstracts from the most difficult sources and writing key and highly involved chapters with the greatest commitment and professionalism.He seemed to check everything - even after publication - and was never slow to point out deficiencies with a directness that could only be forgiven by the succeeding friendly references to Britishmew Zealand sporting interactions. Over many years Janet Freshwater and Alan Cubitt, of the Royal Society of Chemistry, provided us with invaluable help by administering the projects and smoothing the paths of our manuscripts from delivery to publication. Sincere thanks are extended for all their work on behalf of all the contributors. R. J. Ferrier December 2002
Contents
Chapter 1 Introduction and General Aspects
1
2
References
4
Chapter 2 Free Sugars
1 Synthesis 1.1 Tetroses and Pentoses 1.2 Hexoses 1.3 Chain-extended Sugars 2 Reactions
10
3 Other Aspects
11
References
12
Chapter 3 Glycosides and Disaccharides
1 0-Glycosides 1.1 Synthesis of Monosaccharide Glycosides 1.2 Synthesis of Glycosylated Natural Products and Their Analogues 1.3 Glycosides Isolated from Natural Products 1.4 Synthesis of Disaccharides and Their Derivatives 1.5 Disaccharides Containing Sugar Analogues or with Anomalous Linking 1.6 Reactions, Complexation and Other Features of 0-G1ycosides
14
14 14 24 27 29 37 37
2 S- and Se-Glycosides
38
3 C-Glycosides 3.1 General
40 40
Carbohydrate Chemistry, Volume 34 0 The Royal Society of Chemistry, 2003 vii
...
Contents
Vlll
3.2 Pyranoid Compounds 3.3 Furanoid (and Pyrrolidine) Compounds
41 48
References
51
Chapter 4 Oligosaccharides
62
1 General
62
2 Trisaccharides 2.1 General 2.2 Linear Homotrisaccharides 2.3 Linear Heterotrisaccharides 2.4 Branched Homotrisaccharides 2.5 Branched Heterotrisaccharides 2.6 Analogues of Trisaccharides and Compounds with Anomalous Linking
64 64 64 65 67 67
3 Tetrasaccharides 3.1 Linear Homotetrasaccharides 3.2 Linear Heterotetrasaccharides 3.3 Branched Homotet rasaccharides 3.4 Branched Heterotetrasaccharides 3.5 Analogues of Tetrasaccharides and Compounds with Anomalous Linking
69 69 69 70 70
4 Pentasaccharides 4.1 Linear Homopentasaccharides 4.2 Linear Heteropentasaccharides 4.3 Branched Homopentasacharrides 4.4 Branched Heteropentasaccharides 4.5 Analogues of Pentasaccharides and Compounds with Anomalous Linking
72 72 72 73 73
5 Hexasaccharides 5.1 Linear Hexasaccharides 5.2 Branched Hexasaccharides 5.3 Branched Heterohexasaccharides 5.4 Analogues of Hexasaccharides
75 75 75 75 76
6 Heptasaccharides
77
7 Octasaccharides
77
8 Nonasaccharides
78
68
71
74
ix
Contents
9 Higher Saccharides
78
10 Cyclodextrins 10.1 General Matters 10.2 Branched Cyclodextrins 10.3 Cyclodextrin Ethers 10.4 Cyclodextrin Esters 10.5 Amino Derivatives 10.6 Thio Derivatives 10.7 Oxidized Derivatives
80 80 80 80 81 82 82 83
References
83
Chapter 5 Ethers and Anhydro-sugars
91
1 Ethers 1.1 Methyl Ethers 1.2 Other Alkyl and Aryl Ethers 1.3 Silyl Ethers
91 91 91 93
2 Intramolecular Ethers (Anhydro-sugars) 2.1 Oxiranes 2.2 Other Anhydrides
93 93 93
References
93
Chapter 6 Acetals
95
1 Synthesis
95
2 Hydrolysis and Reductive Ring-opening
96
3 Other Reactions and Properties
97
References
98
Chapter 7 Esters
100
1 Carboxylic and Thiocarboxylic Esters 1.1 Synthesis 1.2 Natural Products
100 100 104
2 Phosphates and Related Esters
105
3 Sulfates and Related Esters
108
Contents
X
4 Sulfonate Esters
110
5 Other Esters
110
References
112
Chapter 8 Halogeno-sugars
115
1 Fluoro-sugars
115
2 Chloro-, Bromo- and Iodo-sugars
115
References
117
Chapter 9 Amino-sugars
118
1 Natural Products
118
2 Syntheses 2.1 By Epoxide Ring Opening 2.2 By Nucleophilic Displacement 2.3 By Amadori Reaction 2.4 From Azido-sugars 2.5 From Nitro-sugars 2.6 From Unsaturated Sugars 2.7 From Aldosuloses and Oximes 2.8 From Chiral Non-carbohydrates 2.9 From Achiral Non-carbohydrates
118 118 119 121 121 122 122 124 125 126
3 Reactions and Derivatives 3.1 Interconversion Reactions 3.2 N-Acyl and N-Carbamoyl Derivatives 3.3 Urea, Thiourea, Isothiocyanato and Guanidino Derivatives 3.4 N-Alkyl, N-Alkenyl and N-Glycosyl Derivatives 3.5 Lipid A Analogues
128 128 128
4 Diamino-sugars
131
References
133
Chapter 10 Miscellaneous Nitrogen-containing Derivatives 1 Glycosylamines and Related Glycosyl-N-bonded Compounds 1.1 Glycosylamines and Glycosylammonium Salts
129 130 130
136
136 136
Contents
xi
1.2 Glycosylamides Including N-Glycopeptides 1.3 N-Glycosyl-carbamates, -ureas, -isothiocyanates, -thioureas and Related Compounds
139 141
2 Azido-sugars 2.1 Glycosyl Azides and Triazoles 2.2 Other Azides and Triazoles
143 143 144
3 Nitro- and Nitroso-sugars
145
4 Oximes, Hydroxylamines and Nitrones
146
5 Nitriles, Tetrazoles and Related Compounds
147
6 Hydrazines, Hydrazones and Related Compounds
147
7 Other Heterocycles
150
References
153
Chapter 11 Thio-, Seleno- and Telluro-sugars
157
1 Thiosugars 1.1 Monosaccharides 1.2 Di- and Oligo-saccharides
157 157 162
2 Seleno- and Telluro-sugars
163
References
164
Chapter 12 Deoxy-sugars
166
References
167
Chapter 13 Unsaturated Derivatives
169
1 General
169
2 Pyranoid Derivatives 2.1 1,2-Unsaturated Compounds and Related Derivatives 2.2 2,3-Unsaturated Compounds 2.3 Other Unsaturated Compounds
169 169 170 171
3 Furanoid Derivatives
171
xii
Contents
4 Acyclic Derivatives
172
References
173
Chapter 14 Branched-chain Sugars
175
k
1 Compounds with a C-C-C Branch-point I
0
1.1 Branch at C-2 or C-3 1.2 Branch at C-4
R 2 Compounds with a C-C-C Branch-point (X =N or S) I X
P
3 Compounds with a C-C-C Branch-point I
H
3.1 Branch at C-2 3.2 Branch at C-3 3.3 Branch at C-4 or C-5
I:
175 175 178 179
180 180 182 183
4 Compounds with a C-C-C Branch-point
184
R R II 5 Compounds with a C-C-C or C=b-C Branch-point
184
References
185
I
R
Chapter 15 Aldosuloses and Other Dicarbonyl Compounds
188
1 Aldosuloses 2 Other Dicarbonyl Compounds
188 188
References
Chapter 16 Sugar Acids and Lactones
1 Aldonic Acids, Aldaric Acids and Their Amides, Lactones and Lactams
189 190
190
...
Contents
Xlll
2 Ulosonic Acids
193
3 Uronic Acids
195
4 Ascorbic Acids
197
References
198
Chapter 17 Inorganic Derivatives
200
1 Carbon-bonded Phosphorus Derivatives
200
2 Other Carbon-bonded Derivatives
201
3 Oxygen-bonded Derivatives
201
4 Nitrogen-bonded derivatives
203
References
203
Chapter 18 Alditols and Cyclitols
205
1 Alditols and Derivatives 1.1 Alditols and Derivatives 1.2 Anhydro-alditols 1.3 Monomeric Cyclic Imino-alditols 1.4 Fused-ring and Bicyclic Azasugars 1.5 Azasugar-containing Di- and Tri-saccharides
205 205 207 211 223 224
2 Cyclitols and Derivatives 2.1 Cyclopentane Derivatives 2.2 Inositols and Related Compounds 2.3 Inositol Phosphates and Derivatives 2.4 Carba-sugars 2.5 Aminoglycoside Antibiotics 2.6 Quinic Acid Derivatives 2.7 Other Cyclitol Derivatives
226 226 229 231 234 237 239 239
References
241
Chapter 19 Nucleosides
248
1 General
248
2 Synthesis
248
Contents
xiv
Anhydro- and Cyclo-nucleosides
25 1
Deoxynucleosides
252
Halogenonucleosides
255
Nucleosides with Nitrogen-substituted Sugars
255
Thio- and Seleno-nucleosides
257
Nucleosides with Branched-chain Sugars
260
Nucleosides of Unsaturated Sugars and Dialdosuloses
264
10 C-Nucleosides
265
11 Carbocyclic Nucleosides
266
12 Nucleoside Antibiotics
271
13 Nucleoside Phosphates and Phosphonates 13.1 Nucleoside Mono- and Di-phosphates, Related Phosphonates and Other Analogues 13.2 Cyclic Monophosphates and Their Analogues 13.3 Nucleoside Triphosphates and Their Analogues 13.4 Nucleoside Mono- and Di-phosphosugarsand Their Analogues 13.5 Small Oligonucleotides and Their Analogues
27 1 271 274 275
275 277
14 Oligonucleotide Analogues with Phosphorus-free Linkages
28 1
15 Ethers, Esters and Acetals of Nucleosides 15.1 Ethers 15.2 Esters 15.3 Acetals
283 283 284 286
16 Other Types of Nucleoside Analogue
286
17 Reactions
289
References
292
Chapter 20 Enzymes in Mono- and Oligo-saccharide Chemistry 1 General
303 303
xv
Contents
2 Enzymes in Synthesis 2.1 Aldolases and Ketolases 2.2 Glycosidases 2.3 Glycosyltransferases 2.4 Lipases and Acyl Transferases 2.5 Sulfotransferases 2.6 Coupled, Multi-Enzymatic and Whole Cell-based Syntheses
303 303 304 307 308 309
3 Enzyme Mechanisms
312
4 Other Enzymatic Modifications
314
5 Miscellaneous
315
References
316
Chapter 21 Structural and Quantitative Analytical and Separatory Methods
309
322
1 Computational Methods
322
2 Spectroscopy 2.1 NMR Spectroscopy 2.2 IR Spectroscopy 2.3 Mass Spectrometry 2.4 Other Spectroscopic Methods
323 324 328 329 330
3 Other Analytical Methods 3.1 X-Ray Crystallography 3.2 Physical Measurements
330 330 331
4 Separatory Methods 4.1 Chromatography 4.2 Electrophoresis
331 331 332
References
333
Chapter 22 Carbohydrates in Chiral Organic Synthesis
338
1 Carbocyclic Compounds
338
2 y- and &Lactones
342
3 Macrolides and Their Constituent Segments
345
xv
Contents
xvi
4 Other Oxygen Heterocycles
346
5 Nitogen and Sulfur Heterocycles
351
6 Acyclic Compounds
356
7 Carbohdrates as Chiral Auxiliaries and Catalysts 7.1 Carbohydrate-derivedAuxiliaries 7.2 Carbohydrates as Chiral Catalysts
357 357 36 1
References
364
Author Index
367
Abbreviations
The following abbreviations have been used: Ac Ade AIBN All Ar Ara ASP BBN Bn Boc Bu Bz CAN Cbz CD Cer CI CP CYt Dahp DAST DBU DCC DDQ DEAD DIBALH DMAD DMAP DMF DMSO Dmtr e.e. Ee ESR Et
acetyl adenin-9-yl 2,2-azobisisobutyronitrile ally1 aryl arabinose aspartic acid 9-borabicyclo[3.3.3lnonane benzyl t-but oxycarbonyl butyl benzoyl ceric ammonium nitrate benzyloxycarbonyl circular dichroism ceramide chemical ionization cyclopentadienyl cytosin- 1-yl 3-deoxy-~-arabino-2-heptulosonic acid 7-phosphate diethylaminosulfur trifluoride 1,8-diazabicyclo[5.5.01undec-5-ene dicyclohexylcarbodi-imide
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
diethyl azodicarboxylate di-isobutylaluminium hydride dimethyl acetylenedicarboxylate 4 4dimethy1amino)pyridine N,N-dimeth ylformamide dimethyl sulfoxide dimethoxy t rit yl enantiomeric excess 1-et hoxyethyl electron spin resonance ethyl xvii
Abbreviations
xviii
FAB Fmoc Fru FTIR Fuc Gal GalNAc GLC Glc GlcNAc GlY Gua HeP HMPA HMPT HPLC IDCP Ido Im IR Kdo LAH LDA Leu LTBH LYX Man mCPBA Me Mem Mmtr Mom Ms MS NAD NBS NeuNAc NIS NMNO NMR NOE ORD PCC PDC Ph Phe
fast-atom bombardment 9-fluorenylmethylcarbonyl fructose Fourier transform infrared fucose galactose 2-acetamido-2-deoxy-~-galactose gas-liquid chromatography glucose 2-acetamido-2-deoxy-~-glucose glycine guanin-9-yl L-glycero-D-rnanno-heptose hexamethylophosphoric triamide hexamethylphosphorous triamide high performance liquid chromatography iodonium dicollidine perchlorate idose irnidazolyl infrared 3-deoxy-~-manno-2-octu~osonic acid lithium aluminium hydride lithium di-isopropylamide leucine lithium triethylborohydride lyxose mannose rn-chloroperbenzoic acid methyl (2-methoxyethoxy)methyl monomethoxytrityl methoxymethyl methanesulfonyl(mesyl) mass spectrometry nicotinamide adenine dinucleotide N-bromosuccinimide N-acetylneuraminic acid N-iodosuccinimide N-methylmorpholine N-oxide nuclear magnetic resonance nuclear Overhauser effect optical rotatory dispersion pyridinium chlorochromate pyridinium dichromate phenyl phenylalanine
xix
Abbreviations
Piv Pmb Pr Pro p.t.c. PY Rha Rib Ser SIMS TASF Tbdms Tbdps Tipds Tips Tf Tfa TFA THF ThP Thr Thy Tips TLC Tms TPP TPS Tr Ts Ura UDP UDPG
uv XYl
pivaloyl p-methoxybenzyl ProPYl proline phase transfer catalysis p yridine rhamnose ribose serine secondary-ion mass spectrometry tris(dimethylamino)sulfonium(trimethylsily1)difluoride t-but yldimethylsilyl t-butyldiphenylsilyl tetraisopropyldisilox-1,3-diyl triisopropylsilyl trifluoromethanesulfonyl (triflyl) trifluoroacetyl trifluoroacetic acid tetrahydrofuran tetrah ydropyranyl threonine thymin-1-yl 1,1,3,3-tetraisopropyldisilox-1,3-diyl thin layer chromatography trimethylsilyl triphenylphosphine tri-isopropylbenzenesulfonyl triphenylmethyl (trityl) t oluene-p-sulfonyl (t0syl) uracil-1-yl uridine diphosphate uridine diphosphate glucose ultraviolet xylose
1 introduction and General Aspects
This year saw the publication of a triple issue (numbers 7-9) of Glycoconjugate Journal highlighting 'Glycobiology at the Millennium, a look back and a glance ahead'.' Topics covered range from an appreciation of A. Kabat (Feizi and Lloyd) and affinity enhancement of lectin-carbohydrate interactions (Lee and Lee) to carbohydrates as future anti-adhesion drugs for bacterial disease (Sharon and Ofek). A symposium issue of Journal of Carbohydrate Chemistry features a collection of articles from the First Euroconference on Carbohydrates in Drug Research? A special issue of Chemical Reviews has been published entitled 'Frontiers in Carbohydrate Research', and sub-titled by the guest editor (J.K. Bashkin) 'Carbohydrates - A Hostile Scientific Frontier Becomes Friendlier'.3 Amongst other topics, many of which are referred to at the beginning of relevant chapters, this issue covers solid-phase oligosaccharide synthesis and combinatorial carbohydrate libraries (Seeberger and Haase); intramolecular 0-glycoside formation (Schmidt and co-workers),5 enzyme-based and programmable onepot strategies for synthesis of complex carbohydrates and glycoconjugates (Koeller and Wong: who have written a further review on this topic') and theoretical approaches and experimental validation of studies on the structure, conformation and dynamics of bioactive oligosaccharides (Imberty and Perez).' A review from Zechel and Withers, entitled 'Glycosidase Mechanisms: Anatomy of a Finely-tuned Catalyst', addresses issues of transition state structure, substrate distortion, acid-base catalysis and trapping of covalent intermediates? Winchester and Fleet have reviewed modification of glycosylation of glycoconjugates as a therapeutic strategy;" the use of glycosphingolipid synthesis inhibitors as therapy for glycolipid storage disorders has been also reviewed." The glycan repertoire of genetically modified mice has been analysed by nano-NMR spectroscopy - a key step on the way to understanding the role of glycosylation in uiuo.'* At the whole-cell level, synthetic N-glycolylmannosamine pentaacetate has been used to prime N-glycolylneuraminic acid formation in neural cell cultures and hence alter cell phen~type.'~ Synthetic heparin-diazeniumdiolate conjugates have been shown to act as inhibitors of thrombin-induced blood coagulation by virtue of their ability to generate nitric ~ x i d e .A' ~comprehensive, and comprehensible, survey of topical issues in glycobiology appears in Essentials of Glycobi~logy.'~ The synthesis and biological activity of glycolipids, with a focus on ganglioCarbohydrateChemistry,Volume 34
0 The Royal Society of Chemistry,2003
1
2
Curbohydrate Chemistry
sides and sulfatide, has been reviewed.16 Extensive studies at the forefront of chemical synthesis, detailing the successful total synthesis of the oligosaccharide antibiotic everninomycin 1,have been reported by Nicolaou and co-w~rkers.'~~'~ The use of olefin metathesis in carbohydrate chemistry has been ~eviewed.'~.~~
o% HO
Me'
bMe
'OH
1
Combinatorial methods have been used to generate penta- and hexa-peptides with monosaccharide-recognition ability.21A number of review articles have appeared concerning solution and solid-phase approaches to the generation of carbohydrate-based combinatorial l i b r a r i e ~ . The ~ ~ - use ~ ~ of anomeric radicals in the synthesis of 0-and C-glycosides has been as have the conformations of the radicals and their reactions under reductive c ~ n d i t i o n sAn . ~ ~extensive review of iodine and iodine-based reagents in carbohydrate chemisry has appeared.** Last year saw the death of Professor Guy Dutton, well known for his leading work on polysaccharide structural analysis; his obituary has appeared.29 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
13. 14. 15.
16.
Various authors, Glycoconjugate J., 2OOO,l7,437-668. Various authors, J. Curbohydr. Chem., 2OOO,19,419-657. Various authors, Chem. Rev., 2000,100,4265-471 1. P.H. Seeberger and W.-C. Haase, Chem. Rev., 2000,100,4349. K.-H. Jung, M. Muller and R.R.Schmidt, Chem. Rev., 2000,100,4423. K.M. Koeller and C.-H. Wong, Chem. Reu., 2000,100,4465. K.M. Koeller and C.-H. Wong, Glycobiology, 2000,10,1157. A. Imberty and S. Perez, Chem. Rev., 2000,100,4567. D.L.Zechel and S.G. Withers, Acc. Chem. Res., 200,33,11. B. Winchester and G.W.J. Fleet, J. Carbohydr. Chem., 2000,19,471. C.J. Tifft and R.L. Proia, Glycobiology, 2000,10, 1249. A.E. Manzi, K. Norgard-Sumnicht, S. Argade, J.D. Marth, H. van Halbeek and A. Varki, Glycobiology, 2000,10,669. B.E. Collins, T.J. Fralich, S. Itonori, Y. Ichikawa and R.L.Schnaar, Glycobiology, 2000,10,11. J.E. Saavedra, D.L. Mooradian, K.A. Mowery, M.H. Schoefisch, M.L. Citro, K.M. Davies, M.E. Meyerhoff and L.K. Keefer, Bioorg. Med. Chern.Lett., 2000,10,751. Essentials of Glycobiology, 1999, ed. A. Varki, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York. T. Ikami, H. Ishida and M. Kiso, Methods Enzymol., 2000,311,547 (Chem. Abstr., 2000,132,265 348).
1: Introduction and General Aspects
17.
18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
3
K.C. Nicolaou, H.J. Mitchell, H. Suzuki, R.M. Rodriguez, 0. Baudoin and K.C. Fylaktakidou, Angew. Chem. Int. Ed. Engl., 2000,39,3334,3340,3345. K.C. Nicolaou, H.J. Mitchell, R.M. Rodriguez, K.C. Fylaktakidou, H. Suzuki and S.R. Conley, Chem. Eur. J., 2000,6, 3149. N. Sugimoto, D. Miyoshi and J. Zou, Chem. Commun., 2000,2295. K. Fukase, Kagaku Kogyo, 2000,51,232 (Chem. Abstr., 2000,132,265-351). T . Kanemitsu and 0. Kanie, Trends Glycosci. Glycotechnol., 1999,11,267 (Chem. Abstr., 2000, 132,237 246). M.J. Sofia, Annu. Rep. Comb. Chem. Mol. Diversity, 1999,2,41 (Chem. Abstr., 2000, 132,208 007). H. An and P.D. Cook, Chem. Rev., 2000,100,331 1. R. Roy and S.K. Das, Chem. Commun., 2000,519. A. Furstner, Angew. Chem. Int. Ed. Engl., 2000,39,3013. J. Jimenez-Barbero,J. F. Espinosa, J.L. Asensio, F.J. Canada and A. Poveda, Adu. Carbohydr. Chem. Biochem., 2000,56,235. J.P. Praly, Adu. Carbohydr. Chem. Biochem., 2000,56,65. A.R. Vaino and W.A. Szarek, Adv. Carbohydr. Chem. Biochem., 2000,56,9. H. Parolis, Adu. Carbohydr. Chem. Biochem., 2000,56, ix.
2
Free Sugars
1
Synthesis
1.1 Tetroses and Pentoses. - A new synthesis of 2-0-benzyl-3,4-0-isopropylidene-D-erythrose. (2) from 2,3-O-isopropylidene-~-glyceraldehyde involved chain-extension by use of methyl tolyl sulfoxide, followed by benzylation of the new hydroxyl group to give 1. Quantitative transformation of the sulfoxide to a formyl group (1-2) was achieved by exposure to lutidine-trifluoroacetic anhydride, then aq. sodium hydrogen carbonate.’ Compound 3 was prepared from commercially available (R)-(+)-5-hydroxymethyl-5H-furan-2-one by 0-benzylation and subsequent conjugate addition of (PhMe2Si)2Cu(CN)Li2, and converted to 2-deoxy-~-ribose(5) uia the 2-deoxy-~-ribonolactone derivative 4.2 2’-Deoxy-~-ribose 5-phosphates 13Clabelled at C-3 and C-4, and/or at C-5, were prepared in a chemoenzymatic approach by cyclizing appropriately labelled dihydroxyacetone monophosphates with unlabelled acetaldehyde. By use of [13C2]-, [1-I3C]- or [2-13C]acetaldehyde, labels were also introduced at C-1 and/or C-2.3
eo
0
!
1 R=cH$,--:
BnOCH2 3 R=SiMe2Ph 4 R=OH
OH 5
To1
2 R=CHO
1.2 Hexoses. - The de nouo syntheses of enantiopure D- as well as L-hexoses from vinylfuran (see Vol. 33, Chapter 2, Ref. 10)were greatly improved by use of optimal conditions for the required Sharpless catalysed asymmetric dihydro~ylation.4,~ Hetero Diels-Alder cycloaddition of a,p-unsaturated carbonyl compounds and dioxygenated alkenes in the presence of a chiral bisoxazoline-Cu(0Tf)z complex as Lewis acid catalyst furnished hexopyranose precursors in good yields and high enantomeric excess. In the synthesis of the precursor 6 of ethyl tetra-0acetyl-(3-D-mannopyranose outlined in Scheme 1, for example, a 69 YOoverall yield and 99% ee were achieved.6A new route to hex-2-uloses involving boronor, preferably, lithium-enolates is exemplified in Scheme 2. Only 3,4-transCarbohydratechemistry, Volume 34 0 The Royal Society of Chemistry,2003 4
5
2: Free Sugars
OAc
6
Bnd
Scheme 1
products were formed when the chiral lithium amide 7 was used to generate the enolate, with the D-tagatose derivative 8 as the major (69%) and its D-psicose isomer 9 as the minor (8%) product^.^ CHO
8
9
Reagents: i, 7
Scheme 2
A new approach to multiply-protected aminodeoxyhexoses using an Sn(OTf)2-catalysedcross-aldol condensation between lactaldehyde and a tricarbonyliron/a-aminoheptadiene complex is referred to in Chapter 9. The synthesis of L-sugars has received considerable attention: the furfuralderived, optically active, bicyclic enone 10 served as common precursor of L-galactose, L-gulose and L-idose.*Compound 10 was converted in a four step 1,3-enone transposition to its isomer 11, from which the remaining five Laldohexoses (L-allose, L-altrose, L-glucose, L-mannose and L-talose) were obtained.' Several L-hexoses have been synthesized from the appropriate perbenzylated ~-hexono-1,5-lactonesby exposure to BnONH2-Me3Alto give acyclic intermediates (e.g. 12)which ring-closed with inversion at C-5 on treatment with DEAD-TPP. The resulting oximes (e.g. 13) were readily hydrolysed and reduced to the perbenzylated free L-sugars."
NHOBn H'
H'
10 R = 2-naphthyl 11
12
OBn
D-Glucono-1,4-lactone derivative 14 was converted to L-gulose by reductive opening, followed by persilylation and acetal hydrolysis to give diol 15, then primary oxidation and deprotection. Acetal hydrolysis in the presence of silyl
Carbohydrate Chemistry
6
groups was achieved by use of BC13.11In another, as yet incompleted synthesis of L-gulose starting from 2,3,4,6-tetra-0-Tbdms-~-gulono-1,5-lactone, use was made of BC13 in THF for the selective cleavage of the primary Tbdms ether (16+17), to allow the necessary C-6 oxidation (17-18).12 1,2:5,6-Di-O-isopropylidene-P-L-idofuranose, formed on acid treatment of the 1,2:3,5-di-O-acetal (see Chapters 6 and 13 for synthesis),gave the elimination products 19 and 20 on treatment with DAST-pyridine and PDC-Ac20-pyridine, respectively. The former underwent stereo- and regioselective hydroboration to furnish L-altrose, after acid hydrolysis; the latter was converted to L- mannose by catalytic hydrogenation, then deprote~tion.'~.'~ An immobilized L-rhamnose isomerase of Pseudomonas sp. was used to produce L-talose from L-tagatose and D-gulose from D-sorbose in 12 and 10% crystalline yield, re~pective1y.l~ A new formal synthesis of 4-deoxy-~-hexosesfrom (R)-benzylglycidylether is covered in Chapter 12.
TbdmsO 13
OBn
14
OH
15
OTbdms
16 R = CH20Tbdms 17 R = CHZOH 18 R=CHO
19 R = H 20 R = OAC
21 R = Y 22 R = t
ioYoH
Asymmetric dihydroxylation experiments with a-~-xylo-hex-5-enofuranose derivatives (21-22) under a variety of conditions showed that the C-3 substituent (X) plays an important role. 3-Esters 21 (X = OAc or OBz) and the 3-deoxy compound 21 (X = H) gave D-gluco- and 3-deoxy-~-ido-products,respectively, with good selectivity when 'Admix a' was used as the reagent.16
1.3 Chain-extended Sugars. - 1.3.1 Chain-extension at the 'Non-reducing End'. Methyl 2,3,4-tri-0-benzyl-~-erythro-a-~-g~uco-oct1,5-pyranoside and its L-erythro-P-D-gluco-isomer have been synthesized for the first time by cis-hydroxylation of the appropriate 6-C-vinyl-~-and -L-glycero-D-gluco-pyranose derivatives, respe~tively.'~ Homologation of protected dialdohexoses 23 with a-D-gluco-, a-D-galactoand a-D-allo-configurations by use of various (substituted-methy1)magnesium chlorides, has been undertaken. Good L-selectivity was achieved with
2: Free Sugars
7
PhMe2SiCH2MgCl (e.g. 23-24).'' The glycero-~-manno-heptopyranoside-7phosphate analogues 25 were obtained from a dialdehydo-mannopyranoside precursor by reaction with MeP0(0Et)2-n-BuLi,followed by deprote~tion.'~ R OMe
BnO BnO OBn 23 R=CHO
25
CH,SiMe,Ph
26 R' = HOCH2, R2 = Tbdrns
24 R = I O H
Dibromide 27, required for the preparation of doubly homologated analogues of adenosine (see Chapter 19), was obtained by oxidation of 5-deoxy-a-~-allofuranose derivative 26 to the corresponding 6-aldehyde, treatment with Br2C=PPh3and replacement of the silyl by a benzoyl group.2oThe synthesis of the bridged a,P-unsaturated lactone 30 involved Wittig-extension of the dispiroketal-protected 6-aldehydo-D-mannopyranoside 28 to furnish 29, followed by debenzylation with concomitant cyclization by use of FeC13 in dry dichloromethane.2'
LJ
28 R=CHO
29 R = I I / CO,Me
30 31 R?:S:O= 0
, 32 R = $$Iky', Me
33 R = O j
C-Alkylation of mannofuranoside 5,6-cyclic sulfate 31 with n-alkylated lithium dithianes gave chain-extended 7-osulose precursors 32, accompanied by by-products 33 in increasing amounts (0-42%) with increasing alkyl chain length (n = 0-12).22 Cyclic sulfate 34 was opened with lithium trimethylsilyldithiane to furnish ketone 35 after dethioacetalation. Further processing gave derivatives 36, as shown in Scheme the 3-trimethylsilyl-5-(threos-4-yl)-pyrazole 3.23 3-0-Benzyl-6-deoxy-1,2-O-isopropylidene-a-~-~y~o-hexofuranos-5-ulose (37) on treatment with carbon disulfide and methyl iodide under basic conditions afforded a-oxoketene dithioacetal38, which was transformed to pyrazole derivative 39 by exposure to hydrazine hydrate. A 3-deoxy-3,4-unsaturated analogue was similarly ~repared.2~ Conversion of ketone 37 to the Knoevenagel product 40 prior to treatment with CS2-MeI-NaH led to the formation of the sugar 'push-pull-butadiene' 41.25
8
Carbohydrate Chemistry
34
Reagents:
i,TyxI],
H';
35
36 R = H o r M e
ii, 12, CaC03; iii, DMSO, TFAA; iv, RNHNH2
Scheme 3
37 R = M e 38 R = C =
' In a similar vein, the ring-opening of bis-cyclic sulfates by allylamine has resulted in the heterocyclization of various alditols. bis-Cyclic sulfates were prepared from erythritol and a range of pentitols and hexitols by treating the terminal vicinal hydroxyl pairs with thiocarbonyldiimidazole followed by sodium periodate and catalytic ruthenium(II1) chloride. In this way N-allyl-imino-erythritol, -pentitols and -hexitols were produced in moderate Various isomers of 2,5-di(hydroxymethyl)-3,4-dihydroxypyrrolidine(DMDP or 2,5-dideoxy-2,5imino-hexitols) have been analogously synthesized from different stereoisomers of bis-epoxides and cyclic sulfates derived from hex0ses.4~ The well known, D-mannitol-derivedbis-aziridine 37 has been used to prepare 6-amino-6-deoxy-2,5-imino-~-glucit 01 and - 1,5-imino-~-mannitolderivatives 38 and 39 as potential glycosidase inhibitors. Treatment of 37 with acetic acid, or alternatively ally1 alcohol in the presence of an ytterbium catalyst, afforded mono-0-acetylated or -allylated glucitol/mannitol mixtures in 2:1 and 1:2 ratios respectively.4 A novel synthesis of chiral N-hydroxypyrrolidines, namely 1,4-dideoxy-1,4imino-D-galacto-, -gZuco- and -taZo-hexitols, involving the reductive cyclization (with inversion of stereochemistry at C-4) of the oxime derivatives of protected D-gluco-, -galacto-, and -manno-pyranoses respectively, has been reported. E/ZBenzyloximes were produced by treating the 0-benzoyl protected hemiacetals with benzylhydroxylamine hydrochloride, and these were subsequently mesylated at 0 - 5 and reductively cyclized by treatment with dimethylphenylsilane in trifluoroacetic acid. A mechanistic cascade of neighbouring group participation was proposed (Scheme 11).Conversely, reductive cyclization of the oxime derived from the 6-deoxy L-rhamnose furnished a piperidine (1,5,6as the only product.4' trideoxy- 1,5-imino-~-gulo-hexitol) En route to a Sialyl Lewis X analogue containing 1,4,5,6-tetradeoxy-l,4-
214
Carbohydrate Chemistry
v w Boc
Boc
Boc
I
BocHN
I
BnO
BocHN
OBn
OBn 38 R = Ac. All
37
,o,
O%i
OR
OBn
39
BzO.
-
Bn
Ph
PhAoJ BzO
OBz
OBz
OBz
OBz
BzO
Scheme 11
OBZ
imino-D-ido-hexito1in place of an N-acetylgalactosamine residue (see also Section 1 . 9 , the aforementioned imino-hexitol was synthesized in a protected form using the method of Bernotas (see Vol. 24, p. 198, ref. 36) which involves an intramolecular displacement by nitrogen under Mitsunobu conditions!6 Full details of the synthesis of 6-azido-1,6-dideoxynojirimycin 41 (see Vol28, p. 227, ref. 52) from l-amino- 1-deoxy-D-glucitolvia the intermediate azido sugar 40 have been reported together with its conversion to various analogues 42 of DNJ, and the bicyclic iminosugars castanospermine and kifunen~ine.~’ ~NHCO~BU‘
-
--L
40
41
rNu i __c
-0
k0
ii, iii, iv
Q ..O .H
___)
Phor
Reagents: i, NaH; ii, Nu; iii, H+ resin; iv, Ph3P, DEAD Scheme 12
HO OH 44 R = H, Bn, CH2CH20H
-${I
43 Nu = N3, NHBn, OAc,
18: Alditols and Cyclitols
215
1-Deoxymannojirimycin analogues 43 have been prepared from l-amino- 1deoxy-D-glucitol according to Scheme 12. Various functionalities were incorporated at C-6 (in the product) by treating the aziridine precursor with a range of nucleophiles prior to ring-closure by intramolecular displacement of triphenylphospine oxide by nitrogen under Mitsunobu c o n d i t i o n ~ . ~ ~ Bis-epoxides derived from D-glucitol and L-iditol have been used to create 1,6-dideoxy-1,6-imino-~-glucoand -L-ido-hexitols (polyhydroxy azepanes) 44 by their reaction with various primary amines in dioxane at 100 "C followed by appropriate deprotection. These azepanes were found to be modest inhibitors of almond fbglucosidase and moderate inhibitors of various cancer ~ells.4~ The synthesis of 2,5-dideoxy-2,5-imino-~-altro-hexitols 45 and 3'6-dideoxy3,6-imho-~-glycero-~-altro-heptitols 46 from 2,3,5-tri-O-benzyl-~-lyxose has been reported. Chain extension was achieved using Wittig chemistry while nitrogen was introduced by azide displacement of a mesylate group. Reduction of the azide under Staudinger conditions proceeded with concomitant ringclosure by intramolecular ring-opening of an epoxide. The imino-hexitols 45 were obtained from 4,5,7-tri-O-benzylated 46 by lead tetraacetate-mediated cleavage of the a-diol followed by Pd/C catalysed hydr~genation.~'
1.3.2 Cyclization by Reductive Amination of Carbohydrate Substrates. Various l-amino derivatives of 2,5-dideoxy-2,5-imino-~-mannitol (47) have been prepared in excellent yields in two steps from 5-azido-5-deoxy-~-glucofuranose. Reaction of this material with amines in the presence of acetic acid results in a 1-amino-fructopyranose intermediate via an Amadori rearrangement and catalytic hydrogenation of this ketose using Pearlman's catalyst yields the iminomannitols by simultaneous reduction of the azido group and cyclization by reductive amination. l-N-Acylated derivatives 48 proved to be very strong inhibitors of P-glucosidase from Agrobacterium S P . ~ ~ A new procedure for the preparation of deoxynojirimycin analogues bearing
216
Carbohydrate Chemistry
lipophilic substituents at C-1 has been reported starting from 1,2,3,4,6-pentabenzyl-a/~-D-glucosylamine.Stereoselective introduction of an allylic appendage at C-1 was achieved by reaction with allylmagnesium bromide. Subsequent pyridinium chlorochromate oxidation at C-5 and reductive amination using sodium triacetoxyborohydride in acetic acid afforded the a-allylic DNJ analogue (49 R’ = All) with very high diastereoselectivity.Simple transformations of the ally1 group provided access to propyl (50) and methyl ketone (49 R’ = C(0)Me) derivative^.^^ Trihydroxyazepanes 51-54 have been synthesized as potential glycosidase +-manno-, -D-galacto- and -Linhibitors from 6-azido-3,6-dideoxy-~-gluco-, galacto-pyranoses respectively by Pd/C-catalysed hydrogenation in methanol,53 while tetrahydroxyazepanes 55 and 56 were generated from D- and L-chiroinositol, respectively, utilizing a strategy involving isopropylidene protection of the cis-vicinal hydroxyls, periodate cleavage of the remaining trans-diol and double reductive amination of the product using aminodiphenylmethane and sodium cyan~borohydride.~~ 1.3.3 Cyclization by Addition of Amines to Multiple Bonds of Carbohydrate Substrates. A versatile unsaturated aldehydic intermediate derived from D-ribose has been used to synthesize a number of potential glycosidase inhibitors (Scheme 13). Addition of hydroxylamine and then bromine to the enal resulted in the formation of nitrone 57 with 66% diastereoselectivity, and this in turn was readily transformed into various imino-alditols (e.g. 58-60) by nucleophilic attack followed by reduction. A number of these compounds proved to be good inhibitors of a-~-fucosidases.~~
4
d’
0-
‘Yo i, ii
I
Br
O X 0
O X 0 57
Reagents: i, NH20H;ii, Br2
I Bn CH2TMS
p~-HO~
Scheme 13
i
xIfN-
Me HO OH 58 R = H, R’ = CH2NH2 59 R = H.HBr, R’ = H 60 R = OH, R’ = H
~
Bn
H
ii, iii, iv
OH
%l Reagents: i, hu, 1,4-dicyanonapthaIene,PtOH; ii, 9-BBN then NaOH, H202; iii, HCI, MeOH; iv, Pd(OH)2/C,H2 Scheme 14
A novel route to (+)-isofagomine from D-tartaric acid has been reported. In the presence of 1,4-dicyanonapthalene and light an a-trimethylsilylmethylamine radical cation is generated in an advanced alkynitol intermediate (Scheme 14).
18: Alditols and Cyclitols
217
This radical cation adds intramolecularly to the terminal triple bond to produce ring-closed 61 which is subsequently hydroborated and reduced. Enantiomeric (-)-isofagomine may be obtained if the alkynitol derived from L-tartrate is substit~ted.~~ 1-Deoxymannojirimycin has been synthesized with excellent diastereoselectivity in a process based upon a palladium(I1)-catalysedcyclization of an allylic alcohol 62 derived from ~ - m a n n i f o lC-6 . ~ ~ Homologues of 1-deoxynojirimycin and 1-deoxy-L-idonojirimycin (1,5,6-trideoxy-1,5-imino-~-gluco-and - ~ - i d o heptitols) have also been prepared using palladium chemistry. In these reports the protected aminohex-1-enitol63, derived from methyl a-D-ghcopyranoside, was amino-carbonylated in the presence of palladium(I1) chloride to afford a mixture of cyclized products whose composition was dependent upon the reaction conditions utilized. Two of these products, 64 and 65, were reductively transformed into the DNJ and 1-deoxy-L-idonojirimycinhomolgues respective1y.589 A new, shorter synthesis of miglitol [N-(2-hydroxyethyl)-1-deoxynojirimycin] and its conversion to lipophilic prodrugs by coupling with cholesterol derivatives have been reported. Miglitol was synthesized from methyl 2,3,4-tri-0benzyl-6-bromo-6-deoxy-a-~-glucopyranoside via mercuric trifluoroacetate/ potassium bromide mediated intramolecular addition of a benzyloxyethylamino group to the terminal double bond in the advanced intermediate, 6-(ben1,2,6-trideoxy-~-xyZo-hex1-enitol. zyloxyet hylamino)-3,4,5-tri-O-benzylChromatographic separation of the desired D-gluco- from the undesired ~-idobromomercuric imino-hexitol followed by coupling with cholesterol hemisuccinate and deprotective hydrogenolysis afforded the lipophilic conjugate 66.60 As general approach to dideoxy- and trideoxy-iminoalditols, the synthesis of 1,5-dideoxy- and 1,5,6-trideoxy-1,5-imino-~-glucitoland -galactit01 from p-Dglycosides has been reported. Chromium trioxide oxidation of per-0-acetylated methyl p-D-gluco- and -galactosides to give 5-ulosonic acid esters, followed by amination using hydroxylamine yields the (E/Z)-oximes which in turn cyclize to form aldurono-lactams (67-68) under the conditions of catalytic hydrogenation. Borane reduction and final deprotection gives rise to the trideoxyiminoalditols. Interestingly, reductive cleavage of the acetoxy group at C-6 was observed during the hydrogenation step and afforded the 6-deoxy-lactam. If, however, the primary hydroxyl is unprotected and the ester group converted into an acyl hydrazide prior to hydrogenation by reaction with hydrazine, no such deoxygenation was observed? In a search for new glycosidase inhibitors an imino-em-glycal, N-benzyloxycarbonyl-1,2,5-trideoxy-2,5-imino-~-arabino-hex1-enitol (69) has been prepared from 2,3,5-tri-O-benzyl-~-arabinose. Wittig methylenation followed by a double Mitsunobu process, the second using phthalimide, generated (after deprotection) a 5-amino-hex-1-enitol with overall retention of configuration at C-5. This was protected as a carbamate and cyclized using N-iodosuccinimide followed by DBU.62
218
Carbohydrate Chemistry HO
Po
OBn 63
b:
BnO OBn 64 D-glUCO 65 L-id0
AcO
Q?
HO
OH
AcO
66
OAc
67
OAc
68
OBn 69
I .3.4 Modijication of Azasugars. Boron trifluoride-promoted reaction of allyl trimethylsilane with 2,3-O-isopropylideneprotected pyrrolidine sugar analogues has been shown to proceed with 2,3-trans-stereoselectivityto exclusivelyproduce 2-ally1 C-glycoside analogues in moderate to high yields (47-92%). As an example, 1,2-O-isopropylideneprotected 4-amino-4-deoxy-~-arabinose derivative 70 was converted to the imino-arabinitol 71 in 60% yield and with 100% P-selectivity. The substitution was found to occur from the exo-face of the bicyclic aminal derivatives only, and the resulting 1,2-trans-stereoselectivitywas independent of the configuration of the substituents in the ring.63 5-O-tert-Butyldimethylsilyl- 1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-~ribitol has been used to prepare the ‘Immucillins’, aza-C-nucleoside analogues that are potent inhibitors of purine nucleoside phosphorylases. The inosine analogue 72 for example, bearing a 9-deazapurine, has a K iof 0.07 nM against the human enzyme, and was synthesized by the addition of lithiated acetonitrile to C-1 of an imine intermediate derived from the ribitol precursor with subsequent step-wise construction of the deazapurine substituent using conventional chemistry. 5’-Deoxy-, 5’-deoxy-5’-fluoro- and 2’-deoxy deazainosine analogues of 72, as well as the corresponding azasugar analogues of guanosine, were also prepared.64 1,5-Dideoxy-1,5-imino-~-erythro-pentulose hydrate 74 was produced as an Amadori product during the mild acid (pH > 5) hydrolysis of sulfur-linked The pseudo-disaccharide 73 which has an iminosugar at the non-reducing synthesis of 73 is covered in Chapters 9 and 11. O-Acetylated and non-acetylated N-(3’-iodobenzyl)- and N-(3’-iodo-2’propeny1)-deoxynojirimycin derivatives, along with their corresponding 12’1labelled analogues, were prepared for brain uptake studies in rats by simple treatment of 1-deoxynojirimycin with the appropriate alkylating agent.66 Glycopeptidomimetic nojirimycinyl C-(L)-serine76 was prepared with high diastereoselectivityfrom known a-C-ally1 nojirimycin 75 by simple transformation of the allyl group. Ozonolysis followed by chain-extension using a Wittig-Horner reaction with a glycine-derived phosphonate and final hydrogenolysis/hydrogenation afforded the product as a diastereoisomeric mixture with an L/D ratio of 6:1.67
219
18: Alditols and Cyclitols
Cbz I
R
TbsO 'R* OH OH 72
A2
70 R = H, R',R2 = O(CMe2)0 71 R = Allyl, R' = H, R2 = OH F
&H E
t
AcOi
R
AcO QR1
HO OH
HO
73
OH
HO OH OH 74
AcO 75 R = BOC,R' = Ally1 76 R = H, R' = " $ q C o
2 M e
NHBoc
1.3.5 Other Carbohydrate-based Methods. N-Hydroxy-l,4-dideoxy-l,4-iminoarabinitol, 77, has been prepared in nine steps from (*)-3-O-benzylglyceraldehyde. A transketolase mediated reaction was used to establish a pentulose (5-O-benzyl-~-xylulose) with correct absolute stereochemistry, and a 1,2-oxazine was the unexpected product of the acid-catalysed reaction of an aldehydic intermediate with triethylorthoformate (Scheme 15). Reduction of this oxazine with sodium cyanoborohydride in acetic acid, did not effect cleavage of the N - 0 bond, and yielded the N-hydroxypyrrolidine as a single diastereoisomer.6* CHO
koH
CH20Bn
co -
i-iii, ii, iv, v
F
TbsoT :{ibs
vi
OTbs
?Tbs
T b s o r O T b s EtO
vii, vii,
0'
OH 77
F O CHO CH20H Reagents: i, transketolase, Mg2+,pH 7; ii, TbsTf; iii, NH20H; iv, H2, Raney Ni; v, Swern; vi, (EtO)$H, PTSA; vii, NaCNBH3; viii, HF Scheme 15
__t
BnO
Reagents: i, Bu4NCN, DMF, 100 "C; ii, LiAIH4,THF; iii, TsOH, MeOH Scheme 16
'OBn
78
An unusual stereospecific ring contraction has been observed upon attempted substitution of 4-0-activated pentono- 1,5-lactamswith cyanide. The reaction of 4-O-methanesulfonyl-2,3-O-isopropylidene-~-riboor -D-lyxo-1,5-lactams with tetrabutylammonium cyanide gave 4-amino-5-C-cyano-4,5-dideoxy-2,3-0-isopropylidene-L-lyxo- or -~-ribo-1,4-lactamsrespectively (Scheme 16), instead of the expected products of simple S N displacement of mesylate by cyanide. Reduc-
Carbohydrate Chemistry
220
tion and deprotection afforded the corresponding 6-amino- 1,4,5,6-tetradeoxy1,4-imino-~-Zyxo-and -L-ribo-hexitols, of which the latter was found to be a moderate inhibitor of a-~-fucosidase.6~ l-Deoxynojirimycin (DNJ) and 1-deoxygalactostatin were reportedly prepared from trans-alkoxyaminocyclopentitols78, albeit in poor yield, by reductive ring expansion using lithium aluminium hydride in THF to afford the per-O-benzyl derivatives as minor (~30%)products, followed by hydrogenolytic debenzylation in ethanolic HCl.70The syntheses of 78 from D-glucose and -galactose are covered in Section 2.1. As exemplificationsof a new route to polyhydroxypiperidines, the 6-amino- 1deoxynojirimycin (DNJ) analogues 79 and 80 were synthesized as shown in Scheme 17 from a xylo-pentadialdose (obtained by the action of periodate on 1,2-O-isopropylidene-~-~-g~ucofuranose) by a novel condensative cyclization with (R)-( )-phenylglycinol and potassium cyanide in the presence of zinc bromide to afford the thermodynamically more stable diastereoisomeric bicycles illustrated (45% and 5-1 5% respectively). Catalytic hydrogenation of these compounds resulted in the simultaneous reduction of the cyano group and hydrogenolysis of the chiral appendage.7l
+
OH OH 80 79 Reagents: i, (R)-(+)-phenylglycinol, H20, KCN, citric acid buffer; ii, ZnBr2, MeOH; iii, HP,Pd/C, 10 bar, EtOH, HCI Scheme 17
1.3.6 Syntheses from Non-Carbohydrate Sources. The Birch reduction of an N-protected 2-carboxymethyl substituted pyrrole and subsequent quench with an appropriate electrophile (e.g. methyl 2,3,4-tri-O-benzyl-6-deoxy-6-iodo-a-~glucopyranoside) affords a simple route to N-protected 2,2-disubstituted dihydropyrroles 81. These can be further elaborated into the corresponding 4-substituted imino-ribitols 82 in good overall yield by a simple strategy of reduction, acetylation, syn-dihydroxylation and d e p r ~ t e c t i o n . ~ ~ A [5-14C]-labelled analogue of 1,4-dideoxy-1,4-imino-~-arabinitol,a potent a-glucosidase inhibitor, was conveniently prepared in a one-pot synthesis by ''C-cyanosilylation of (3R,4R)-3,4-dibenzoyloxy-3,4-dihydro-2H-pyrrole 83 using an inexpensive mixture of potassium cyanide and chlorotrimethylsilane.
221
18: Alditols and Cyclitols
An epimeric mixture of 2-cyanopyrrolidines resulted and upon separation of the desired isomer, the arabinitol derivative was produced by acid hydrolysis and borane-dimethyl sulfide reduction of the so-formed carboxylic Two total syntheses of pyrrolidine alkaloids have been reported. (-)Codonopsinine (85), an imino-pentitol which exhibits antibiotic and hypotensive activity, has been synthesized in seven steps in 16% overall yield from dihydropyrrole 84.74The enantioselective synthesis of the potent antifungal agent ( +)-preussin (87)has also been achieved from L-phenylalaninederivative 86. The pyrrolidine skeleton was established by hydrogenolysis of an intermediate oxazoline and subsequent diastereoselective reductive cyclization of the resultant aminoketone using Pearlman’s catalyst.75
/ .HCI
R-& ,
T
r
O C02Me B
Me
@
Me
I
HO MeO2C
C6H40Mep
-
OH OH 81 82 R = OAc, 6-deoxy-6-yl-a-D-GlcpOMe
OBz
83
84
OH
85
-.
To1 s”O
;‘I
86
87
88
89
Two syntheses of iminoalditols from chiral1,2-oxazines by catalytic reduction have appeared. A novel asymmetric hetero-Diels-Alder reaction of a l-p-tolylsulfinyl-1,3-diene with benzyl nitrosoformate provides access to 89, an optically pure 1,4-imino-~-ribitolderivative. The cycloaddition yields 1,2-oxazine 88 with complete regio- and diastero-selectivity,and in a very neat single synthetic step, a dihydroxylated derivative of this adduct is converted into an enatiomerically pure pyrrolidine by reduction under Pd/C. This ‘reduction’encompasses hydrogenolysis of the benzyl group to yield a carbamic acid, decarboxylation, hydrogenolysis of the N-0 bond, cleavage of the sulfonyl auxiliary with concomitant formation of an unstable aminoaldehyde, cyclization and final hydrogenation of the resulting imine?6Full details of the conversion of chiral 1,2-oxazines (e.g. 90), derived from hetero-Diels-Alder cycloaddition of an a-chloronitroso-D-mannofuranosyl derivative with sorbaldehyde dimethyl acetal (see Vol. 31, p. 229, ref. 50) into 1,2,5-trideoxy-2,5-imino-~-a~ditols such as 91 have also been reported. Compound 91 is a potent a-D-galactosidase and a-L-fucosidaseinhibitor with Kj values of 9 and 5 pM re~pectively.7~ Several papers which detail the syntheses of isofagomine, its stereosiomers and various 3-susbstituted analogues by heterocycle modification have appeared. ( f)-Isofagomine (92) and its (3,4-) stereoisomers (5-hydroxymethyl-3,4-dihydroxypiperidines) have been prepared in short syntheses from arecoline. Osmylation or epoxidation and hydrolytic ring-opening (mCPBA or methyltri-
222
Carbohydrate Chemistry Me
C02Bn
HO--
Ho%Me 91
90
fluoromethyldioxirane/perchloric acid) carried out on the tetrahydropyridine intermediate 93 provided access to the four stereoi~omers.~~ Piperidinone 94 has been used as a precursor to 3-substituted isofagomine analogues. A series of twelve 3,4,5-trisubstituted piperidines were synthesized via three key intermediates as depicted in Scheme 18. The free acids 95 were obtained by acid treatment, while the 3-deoxy-3-hydroxymethyl derivatives 96 were obtained by lithium borohydride reduction prior to acid treatment. Reaction of the free acids with diphenylphosphoryl azide produced highly reactive isocyanides, via Curtius rearrangement of the initially formed acyl azides, which underwent spontaneous intramolecular reaction to produce the cyclic carbamates 97. Hydrolyses of these carbamates in refluxing HCl gave the corresponding 3-amino-isofagomine derivatives 98.79 In a succeeding report 3-deoxy- and 3-C-hydroxymethylisofagomines 99 and 100, respectively, were also synthesized from 94.80The cyclopentenoid building block 101, accessed from the fragmentation of a norbornyl derivative, has been elaborated into isofagomine analogues 102 and 103 by OH
I
HO' R' 'R2 92 R ' = O H , R ~ = H 99 R' = R ~ H = 100 R' = OH, R2 = CH20H
Eto2c6 OR
93
k;. kN
OH
OH
i, ii
Boc I
0
94
97
Reagents: i, LDA, 2-(trimethylsilyl)ethoxymethylchloride (SemCl); ii, H2, Pd/C Scheme 18
Q
rC02Me
101
?'
(k$ I
I
OH 102 R = H, R' = OH 103 R = Bn or H, R' = H
HO OH 104 R = Bn or H, R' = CH20H, R2 = H 105 R = Bn or H, R' = H, R2 = CH20H
18: Alditols and Cyclitols
223
oxidative cleavage of the double bond followed by a strategy incorporating a double displacement of a dimesylate with p-toluenesulfonamide (-102) or a double reductive amination with benzylamine and sodium cyanoborohydride (-.103).81 The same building block 101 was also transformed into altro- and galacto-deoxynojirimycin analogues 104 and 105, respectively, using similar methodology. The glycosidase inhibitory activity of the latter compounds was reported to be moderate-strong.82 1.3.7 Natural Products. Four new broussonetines, M, 0, P and Q (106-log), pyrrolidine alkaloids with fJ-glycosidase inhibitory properties, have been isolated from branches of Broussoneta kazin0ki.8~ 6-C-Butyl-DMDP (dihydroxymethyl dihydroxy pyrrolidine) derivative 110, with an ICsoof 68 pm against almond P-glucosidase, and a-1-C-ethyl-fagomine 111, with an ICSO of 29 pm against bovine liver P-galactosidase, were isolated from Adenophora triphylla sp., along with four known imino-sugars (DMDP, D-AB~,DNJ and DMJ).84 Five new homonojirimycin derivatives (112-116), including two glucosylated pseudo-disaccharides (113 and 115, see also Section lS), and deoxygalactonojirimycin derivative 117 have been extracted from the roots of Adenophora sp.85
OH
13'
106 (M) R = ( C H 2 ) g v O H 107 (0) R=
,\\
109 (Q) R'= (CH2)9 7
OH
13'
0
108 (P) R =
,\\
C4H9
0
OH
OH
OH
OH 110
OH
Et
HO 111
112 113 114 115
~
R2 = P-D-GIc~
OH
6 Rfj @ 13'
0
0
CH20R3 OH R3 = H, R2 = OH R2 = OH,R3 = P-D-GIc~ R2=R3=H R2 = H, R3 = P-D-Glcp
OH 116
H 0 @ c H 9
OH 117
1.4 Fused-ring and Bicyclic Azasugars. - Four new polyhydroxypyrrolizidines, the Hyacinthacines A1, A2, A3 and B3 (118-121 respectively) were isolated from the bulbs of Muscari armeniacum, and their structures Bis-aziridine 37 (see Section 1.3.l), derived from D-mannitol, was converted
2
224
Carbohydrate Chemistry
into oxazolidinone 122by treatment with dilithium nickel tetrabromide followed by silver nitrate in DMF at elevated temperature.44 5-Isoxazolidinone 124 was synthesized from dehydroamino acid 123, which has a pentose sugar moiety at its side-chain, by displacement of the terminal mesylate by hydroxylamine with spontaneous cyclization by intramolecular Michael-like addition. Interestingly, when a tetrose-derived dehydroamino acid was substituted, no cyclization was Improved syntheses of ( )-lentiginosine (125) and (7R)-7-hydroxylentiginosine (126), inhibitors of amyloglucosidases, have been reported. In multistep syntheses based upon a 1,3-dipolar cycloaddition of a pyrrolidine N-oxide derived from L-tartaric acid to 3-buten-l-o1,125 and 126 were prepared in 25% and 37% overall yields from a common indolizidine intermediate. The enantiomers of these compounds could be similarly prepared using D-tartaric acid as a starting Castanospermine analogues 127 and 128 have been synthesized in many steps from a chirally unresolved pyrr~lidinone.~’
+
HLHQ3 R’ 118 119 120 121 PmbO,
R’ R’ R’ R’
k2
R4
= R 3 = R 4 = H, R 2 = O H = OH, R2 = R3 = R4 = H =OH, R2= R 4 = H, R 3 = Me
BocHN*
OBn
0
122
123
= H, R2 = R4 = OH, R3 = Me
wo P
PmbO,*&oMs OPmb
A
,
R’
-9
PmbO’ PmbO it NHCOCF3 124
HO 125 R = H 126 R = O H
127 R’ = R4 = OH, R2 = R3 = H 128 R’ = R4 = H, R2 = R3 = OH
A new strategy has been reported for the preparation of fused azolepiperidinoses 129 using an unprecedented 6-exo-trig cyclization of radical precursors derived from 3-(1,2,3-triazol-1-y1)- and -( 1,2,4-triazol-l-y1)-substituted 3-deoxy-1,2:5,6-di-O-isopropylidene-a-~-glucofuranoses by treatment with tris(trimethylsily1)silanein toluene (Scheme 19).90 Bicyclic polyhydroxylated isoquinuclidines with conformations that mimic the boat-form of pyranosides have been prepared in multiple steps from an achiral pyridinone. These compounds proved to be strong and selective inhibitors of snail fbmannosidase (130 R = H, Ki 20 pm; R = Bn, Ki 0.17 pm)? 1.5 Azasugar-containing Di- and Tri-saccharides.- A number of glycosylated iminoalditols have been isolated from plant extracts. Glycosylated homo-
225
18: Alditols and Cyclitols OR
H;ao R
I %Z-N - k
'O
-
X = N, Y = Z = CHC02Et
X=CH,Y=N,Z=CH
130 R = Bn, H
i
7 X = N,Y = CHC02Et II
X=CH,Y=N
Reagents: i, [(CH3)3Si]3SiH,To1 (0.02 M), 72% (R = H), 94% (R = Ac) ii, [(CH3&3iI3SiH,To1 (0.02 M), 50% (R = H) Scheme 19
nojirimycin 131 has been isolated from the plant Lobelia sessil$olia?* while 113 and 115 were found in the roots of Adenophora ~ p . 9Broussonetine ~ 109 was isolated from branches of Broussonetia k~zinok?~(see Section 1.3.3). The N-linked pseudo-disaccharide 132 has been prepared from imino-D-altrohexitol45 (Section 1.3.1) and this compound was found to be a potent inhibitor of P-galactosidase ( K i3.3 ~ m ) ? ~
4 Hoc& 4
HO
OH CH20R
131 R = P-o-Glcp
NHAc
OH
+OHC%
OBn
HO
OH
R
133 R = 6-yl-P-D-Galp 134 R = 5-yl-P-D-Ribf
132
oqo
R OH HO f l OH
___)
O x 0
Reagents: i, BuLi, (h~le~Si)~NH; ii, LiAIH4; iii, Pd(OH)*/C, H2; iv, TFA Scheme 20
135
Wittig condensation of N-benzyl-2,3,5-tri-O-benzyl1,4-dideoxy-l-formyl-1,4imino-L-Zyxo-and -L-xylo-pentitols with protected ~-galactopyranose-6-or Dribofuranose-5-phosphoranesgave rise to the pyrrolidine-based (1-6)- and (1-5)-aza-C-disaccharides 133 (L-lyxo) and 134 (L-XYZO) respectively after hydrogenation and d e p r ~ t e c t i o nThe . ~ ~(1-3)-aza-C-disaccharide 135, on the other hand, was synthesized as shown in Scheme 20 using a cross-aldol reaction between a 6-formyl-iminoribitol and an anhydro-keto sugar derived from isolevoglucosenoneP6In a novel approach to disaccharide analogues of this type, stereoselective cycloaddition reactions between functionalized cyclic nitrones and sugar alkenes have also been successfully employed. Exemplified in Scheme 21, a nitrone derived in two steps from 2,3-0-isopropyfidene-~-lyxose underwent a 1,3-dipolar cycloaddition with a protected a-D-manno- or -galacto-hept-6-
226
Carbohydrate Chemistry
enopyranose to form an isoxazolidine cycloadduct which was reductively cleaved and deoxygenated to produce aza-C-disaccharides 136.9' In the synthesis of a Sialyl Lewis X analogue, 1,4,5,6-tetradeoxy-1,4-imino-~ido-hexitol (for synthesis see Section 1.3.1) was a-L-fucosylated at the less hindered (C-2) hydroxyl, then P-D-galactosylated at 0 - 3 to produce a non-sulfated precursor to the pseudo-trisaccharide 137.46
NH.HCI
I
0-
+ PgO
OPg-
Pg = protecting group Scheme 21
HO
OMe
OH 136
'OH
""'"T OH 137
2 Cyclitols and Derivatives. - A review on the application of the Pd(I1)catalysed Ferrier (11)carbocyclization in the synthesis of fl-glucosidase inhibitors, cyclophellitol,all the diastereoisomers of inositol, and D-myo-inositol phosphates has been published?* 2.1 Cyclopentane Derivatives. - Carbapentafuranoses have been prepared in high yield from a variety of O-protected hexopyranosides, including a-D-gluco-, P-D-allo-, a-D-manno- and a-D-galacto-pyranosides, via cobalt-catalysed oxygenative radical cyclization of 6-iodo-hex-1-enit01 derivatives. For example, 138, derived from methyl 2,3,4-tri-0-benzyl-6-deoxy-6-iodo-a-~-glucopyranoside, was cyclized with very high diastereoselectivity to the cyclitol 139 using a catalytic Co(sa1en) complex in the presence of air (Scheme 22).99The same iodo-glucoside starting material has also been used to make the bicycle 140. Zinc reduction followed by reaction with a hydrazine carboxylate is thought to afford the transient species 141, the product of a prototropic shift, which cyclizes to the bicycle spontaneously under the reaction condition^.'^ Ring-closing olefin metathesis has been used to effect cyclitol formation. The carba-P-D-arabinofuranose 143lo0and carba-P- and -a-D-arabinofuranosides 1441°1were synthesized by ring-closing metathesis of hept-1,6-dienitols derived from D-arabinose (142, P = Pmb) and D-mannose (142, P = Mom) respectively, by employing Schrock's catalyst followed by stereoselective hydrogenation of the resulting cyclopentene. The syntheses of carba-P-D-xylofuranose and -xylofuranosylamine have been reported starting from 2,3-O-isopropylidene-~-glyceraldehyde and either 2[(tert-but yldimethylsilyl)oxy]furan or N-( tert -but oxycarbony1)-2-[(tert-butyldimethylsilyl)oxy]- 1H-pyrrole respectively. The key reactions in the syntheses (depicted in Scheme 23) are the highly stereoselective boron trifluoride promoted nucleophilic addition of the furan or pyrrole to the aldehyde, and later, the
227
18: Alditols and Cyclitols
LH0+. BnO'
BnO &I
OBn
BnO'
OBn
OBn 138 139 Reagents: i, cat. Co(salen) complex, air Scheme 22
OH =H 143 R' = OH, 144 R' = OMe, R2 = H; R' = H, R 2 = OMe
OBn OBn 142
CHO
b:
20 step) syntheses of 1-0-(1,2-di-O-pentadecanoylphosphatidyl)-~myo-inositol 3,4- and 4,5-bisphosphates and 3,4,5-trisphosphate starting from L-( - )-quebrachitol have also been r e ~ 0 r t e d . I ~ ~ The myo-inositol acceptor 1-0-allyl-2,3,4,5-tetra-O-benzyl-~-myo-inositol was synthesized from meso-2,5-di-O-benzoyl-myo-inositol for use in the total synthesis of a heptaose mimetic, a GPI anchor compound of T. brucei (see Vol. 32, p.71. ref. 156).The inositol was desymmetrized using the bis(spiroketa1)protected intermediate 175 to enable the stepwise glycosylation at 0 - 6 and attachment of a phosphoglyceride moiety at 0-1. Cleavage of the 'dispoke' was effected by oxidizing the thiophenyl substituents with mCPBA and then treating the product disulfone with lithium hexamethyldisilazide in THF.'37In a similar synthesis
233
18: Alditols and Cyclitols \
9
PhS
/
OH OH
HO 175
MntC(0)O OH
HO
OH 176 Reagents: i, Et3B-BuC02BEt2,hexane; ii, Bu2Sn(acac)2,toluene; iii, MntCOCl, NMI Scheme 28 OH
of a pseudohexasaccharide IPG, a myo-inositol building block was again prepared with a view to regioselective glycosylation at 0 - 6 and phosphorylation at 0-1 (see also Chapter 4). Of interest was the use of a boron-tin exchange reaction to achieve a key selective acylation: the 1-0-(-)-menthoxycarbonyl derivative 176 was prepared from myo-inositol according to Scheme 28 to overcome the insolubility problem of myo-inositol in most organic A myo-inositol-containingIPG pseudopentasaccharide bearing the conserved linear structure of GPI anchors was synthesized for intracellular signalling studies. The structure of this IPG is detailed in Chapter 4; the key building blocks were a mannotriosyl donor and an inositol-containing O-6-glucosylated pseudodisaccharide acceptor with the C-1 and C-2 hydroxyls accessible for cyclo-phosphorylation.'39Similarly the rnyo-inositol phosphoglycan fragments 177 found in Leishmania parasites have been synthesized by coupling an inositolcontaining disaccharide with a mannobiosyl donor.'40 The antigenic core of the glycoconjugate lipoarabinomannan (LAM) from Mycobacteriurn tuberculosis, 2,6-dimannosyl-myo-inositol l-phosphate, was synthesized by stepwise regioselective mannosylation at the free C-2- and then at the C-6-hydroxyl in 178. Removal of the l-acetate provided for phosphorylation at the correct New preparative syntheses of 6-0-(2-amino-2-deoxy-a-~-g~ucopyranosyl)-~chiro-inositol l-phosphate and a 1,2-cyclic phosphate derivative have been reported. Differential protection was achieved by initially locking the four equatorial hydroxyls of D-chiro-inositol as cyclic Tipds ethers and then generating a cis-epoxide from the two remaining trans-diaxial hydroxyls under Mitsunobu conditions. Lewis acid catalysed trans-diaxial opening with ally1 alcohol allowed for selective protection at 0-1 and 0-6.142 3-(Hydroxymethy1)-bearing phosphatidylinositol ether lipid analogues 179 (X = P) and carbonate surrogates (X = C) block the phosphatidylinositol 3kinase (PI3-K) enzyme and inhibit cancer cell growth. Chain extension was effected by (Swern) oxidation at C-3, subsequent Wittig methylenation and hydroboration using 9-BBN to afford a separable C-3-epimeric mixture of (hydroxymethyl)inositols.143In another lengthy synthesis from L-( -)-quebrachitol (ca. 20 steps) the 3,4-dideoxy variant 180 of 179 (X = P) was made with the incorporation of two Barton deoxygenation reactions. This dideoxy ana-
234
Carbohydrate Chemistry
logue was found to be 18-fold more potent than its (mono) 3-deoxy counterpart in the inhibition of P13-K.14
HO
? 177 R = R10-y+6)-a-D-Manp(
un
OR 1+3)-a-D-Manp( 1+4)-a-D-Glcp-NH*
OH
0-x-0
AcO OH
HO
OBn 178
f
I
OMe
Ho@,
OC1BH37
R2 179 R = CH20H, R’ = H, R2 = OH, X = P(0H) R = H, R’ = CHzOH, R2 = OH, X = P(0H) R = CH20H, R’ = H, R2=OH, X = C R=H,R’=CH20H,R2=OH,X=C 180 R = CH20H, R’ = R2 = H, X = P(0H)
2.4 Carba-sugars. - Carba-furanoses and carba-furanosides are covered in Section 2.1. The first direct transformation of 1-S-, -Se- and -C-hex-5-enopyranosides into carbocycles with retention of the aglycon has been reported. Phenyl 2,3,4-tri-O-benzyl-6-deoxy-l-thioand -l-seleno-fb~-g~uco-hex-5-enopyranosides were converted into the corresponding cyclitols 181 in over 80% yield by treatment with five equivalents of triisobutylaluminium (TIBAL) in toluene at 50 “C. The 2,4,6-trimethoxyphenyl f3-C-glycoside gave, on the other hand, a mixture of 182 and 183 in a 1.5:l ratio under identical Applying the same chemistry to an a-C-(2-furanyl)-glycosideafforded the cyclitoll84 and this by methylation, was elaborated further into methyl Sa-carba-f3-~-idopyranoside ozonolytic cleavage of the furan moiety and subsequent reduction of the resulting ester group with concomitant O-debenzylation. The enantiomeric 5acarba-P-L-idopyranoside was obtained via a different route from methyl 2,3,4tri-O-benzyl-6-deoxy-~-~-gluco-hex-5-enopyranoside by reaction with isopropoxytitanium(1V) chloride and subsequent elaboration of the resulting carbocycle 185. TIBAL-promoted rearrangement followed by oxidation of the newly formed secondary hydroxyl was a reaction motif used in the generation of the 5’a-carba-disaccharide 186146as well as (1-4) ether-linked di- and trisaccharide mimetics 188 from unsaturated thioglycoside di- and tri-saccharide precursors 187. 2,5-Di-O-benzyl-3,4-O-isopropylidene-~-mann~tol was ring closed to afford a 9:l cis/trans mixture of 189 in high yield by (Swern) oxidation and radical cyclization of the dialdehyde using samarium iodide in tert-butanol. The cisdiastereoisomer was selectively converted into a cis-cyclic sulfate which underwent cleavage upon treatment with potassium tert-butoxide to afford a cyclo14’914*
235
18: Alditols and Cyclitols 0 OBn
BnO OBn
BnO
OBn
BnO 184
182 R' = H, R2 = OH 183 R' = OH, R 2 = H
181 X = S, Se
BnO OBn
OMe OBn
BnO 185
/
BnO OBn
186
188 n = O , l ; X = C H 2 , Y = O 187 n = 0 , 1 ;X = 0, Y = CH2
hexanone derivative. Further development of this intermediate, as shown in Scheme 29, allowed the production of either a Sa-carba- galactose (>9: 1 L-/D-) or a Sa-carba-L-fucopyranosederi~ative.'~~ OBn
OBn
OBn
x;QoKz
y+ O ;-()H yJ(H OH OBn
0
OH
jl/
OBn 189
OBn
-
xrg X
OBn
vi
(::
:
__t
p o B n o r HOBnO
OH
@OH HO OR R = Tbdms
H :2
Reagents: i, Swem; ii, SmI2, Bu'OH; iii, S0Cl2, NEt,; iv, NaIO,, RuCI3; v, Bu'OK then H2S04; vi, Wittig. Scheme 29
The pseudo-sugars 6a-carba-a- (191)and -P-D-fructopyranose(192)have been prepared in six steps from an enzymatically resolved homochiral cyclohexanetrio1 building block via a common olefinic intermediate 190 by varying the dihydroxylation strategy (osmium tetroxide vs. rn-CPBA respe~tively).'~~ Another non-carbohydrate based route to Sa-carba-sugars has been reported which utilizes a 7-norbornanone-derived cyclohexenoid intermediate. The preparation of carba-a- and -g-galacto-, -a-talo- and -a-fucopyranose derivatives were described.' 51 D-Glyceraldehyde has been used as a starting material for the synthesis of pseudo P-D-gulopyranose and -gulopyranosylamine. As detailed in section 2.1 the method shown in Scheme 23 for the synthesis of carba-P-D-xylofuranoseand -xylofuranosylamine was modified by the omission of a C-C cleavage to result in the formation of the above cyclohexane derivatives.'02 and -galactoThe pseudo-sugars 5a-carba-a-~~-fucopyranosylamine
236
Carbohydrate Chemistry
pyranosylamine were made as racemates from known 2,3,4,6-tetra-O-acetyl-5acarba-a-L-glucopyranosyl bromide by standard methods; the amino group was introduced via azide displacement of the bromide, inversion at C-4 was effected by displacement of a mesylate group and deoxygenation at C-6 (in the case of the former) by treatment of a 6-iodo intermediate with tributyltin hydride. The former carba-sugar was found to be a strong inhibitor of bovine kidney afuco~idase.'~~ New syntheses of ( )-valienamine (193) and ( )-valiolamine (194), pseudoaminosugars found in valiolamycins, acarbose and trestatines, have been described starting from a derivative of ~-xylono-1,4-lactonein twelve or more steps,'53and using much the same methodology the same group has reported the first total synthesis of pyralomycin l c (195) from an ~-arabinono-1,4-lactone derivative.lS4The synthesis of an a-hydroxymethyl-substituted a$-unsaturated cyclohexenone intermediate common to all these compounds (with the exception of the stereochemistry of the hydroxyl groups) has been previously described in Vol. 32, p. 357. A preparation of carba-sugars from sugar lactones via spiro aldonic acid orthoesters has been reported. The cyclitol derivative 196, a versatile synthon for the synthesis of valiolamine and related compounds, was synthesized in high overall yield (70% over 4 steps) from 2,3,4,6-tetra-O-benzyl-~glucono- 1,5-lactone according to Scheme 30. Enol ether formation from the sugar ortho ester with trimethylaluminium and the zinc chloride-promoted intramolecular aldol cyclization were the key steps in the ~ynthesis.'~~ Identical methodology used on the corresponding ~-mannono-1,5-lactone gave rise to 197 as the major product (together with 9% of the C-5 epimer) and reduction of this cyclohexanone with sodium borohydride produced a roughly 1:l mixture of the 'anomeric' 5-hydroxy-curba-s~gars.~~~
+
'
+
Q
HO QH*
HO 190
OH 191 R =CH,OH, R' = O H 192 R = OH, R' = CH20H
193 X = NH2
OH 0
OH
OH 194
195 X=Cl*"'
7-
Me
A difluorinated carba-sugar 198 has been synthesized as a potential herbicide in 22% overall yield from D-ribose. The key step is an intramolecular 1,3-dipolar nitrone cycloaddition to generate an isoxazolidine as shown in Scheme 31.'57 Another cycloadditon strategy has been used to generate 1,4-glycosidically linked 'mono-carba-disaccharides'. A dieneophilic aglycon underwent stereospecific Diels-Alder cycloaddition to maleic anhydride and the resulting cycloadduct 199 was elaborated into a Sa-carba-a-~-idopyranoseunit to form the pseudo-disaccharide 200.lS8 In addition to three known gabosines, three new gabosines (L, N and 0: 201-203 respectively) have been detected as secondary metabolites of Streptornyces strains.lS9
237
18: Alditols and Cyclitols
OBn
OBn
OBn
OBn 196 Reagents: i, 2,2-Dimethylpropane-1,3-diol,TmsOMe, TmsOTf, Toluene; ii, AlMe3; iii, Ac20, DMSO; iv, ZnC12, THF/H20 Scheme 30 Bn0-l
197 NHMe
I
@F
OH
OH
OAc
Reagents: i, MeNHOH.HCI,pyridine
198
Scheme 31 0
h-*
x--QoTms
0
AcO
0
& ? )
AcO
OAc 199
-
AcO
-aoAc '
AcO OAc 200
LAC
Ho@H 0
o 201
OH b HO
202
H
O
s o H HO OH 203
2.5 Aminoglycoside Antibiotics. - In a single study fourteen different aminoglycosides of the kanamycin/gentamycin, neomycin and astromycin classes were acetylated with aminoglycoside acetyltransferases from Actinomycete sp. in order to determine the degree of activity retained after acety1ation.l6' The acetylation of istamycin and miconomycin antiobiotics at the 6'-methylamino group by a novel aminoglycoside 6'-acetyltransferase from Actinomycete sp. was also reported.161See also Chapter 20. Neamine analogues have been prepared in several studies in order to explore their potential as small molecule antitumour and anti-HIV agents, as well as bacterial enzyme inhibitors. 5-0-Alkylated neamines with polyamine functionality in the side-chain have been synthesized from 5-0-allylated precursors and these were found to exhibit high binding affinity for oncogene fusion proteins.'62 The acylation of neamines at N-6' with aromatic units was carried out to explore the effect of these substituents on the interaction of neamine aminoglycosides with HIV RNA. Pyrene substituents were found to impart the most effective level
238
Carbohydrate Chemistry
of binding (sub-micromolar) amongst those groups studied.’63The tethering of a neamine aminoglycoside to an adenosine residue by the incorporation of a 6- or 7-carbon (methylene)spacer between 0 - 3 ’ and 0-5”(of the ribofuranose moiety) resulted in high binding affinities for bacterial 3’-phosphotransferases. These enzymes are known to inactivate aminoglycoside antibiotics, and their inhibition would serve to depress bacterial resistance to this class of compounds.’64 Various analogues of neomycin B have also been synthesized in an effort to develop inhibitors of viral RNA. Compounds 204 and 205 were made from neamine, again via a 5-0-allylated precursor. Oxidative cleavage and reduction of the resulting aldehyde with sodium borohydride gave the acceptor 206 which was then glycosylated with the appropriately protected glycosyl donors (see also Chapter 3). Neither 204 nor 205 were found to be effective as anti-HIV agents.165 Two analogues of neomycin B, each lacking one of the 2,6-diamino-sugars were prepared for binding studies by ribofuranosylation (at 0-5) of a 4-0-aminoglycosyl inositol ‘disaccharide’ obtained from paromomycin, and by the coupling of a cyclitol derivative (at 0-5) with an appropriate 3-0-diaminoglycosylribofuranosyl acetate.’66The neomycin-acridine conjugate 208 was found to be a potent inhibitor of Rev-Rev Response Element (RRE) binding. Synthesized from neomycin B in 5 steps according to Scheme 32, this compound has definite anti-HIV p~tential.’~’
HO Q O O H 2
NH2/J RO
OH
H2Nv
204 R =
6; OHOH
205 R =
Ho$H2 HO
OH
207 R =
OH
OH
HO
206 R = H
HO
Kanamycin A has also received some attention. Three analogues 207 each containing a 6-amino-6-deoxyglycofuranose moiety have been prepared by coupling with appropriate glycosyl chlorides and fluorides. All three compounds, however, were inactive in antibacterial screens.’68 A new guanidinylation reagent, N,N-di-Boc-N’-triflylguanidine, has been used to efficiently convert multiamine-containing aminoglycoside antibiotics into fully guanidinylated analogues in the presence of water under mild conditions. ‘Guanidinylglycoside’analogues of kanamycin A and B, paromomycin, tobramycin and neomycin B were prepared in this way; the last two were found
18: Alditols and Cyclitols
239
OH 208 Reagents: i, B0c20, DMF, Et3N, H20; ii, triisopropylbenzenesulfonylchloride, pyr; iii, 2-aminoethanethiol, EtOH, EtONa; iv, 9-phenoxyacridine, phenol; v, 4M HCI, dioxane, 1,2-ethanedithioI Scheme 32
to possess HIV inhibitory activities 100-fold greater than their parent aminoglyc~sides.'~~ The chemistry of the guanidinylation reaction is covered in more detail in Chapters 9 and 10. 2.6 Quinic Acid Derivatives. - Two quinic acid derivatives have been isolated from natural sources. 1,3-Di-O-trans-feruoylquinicacid (209) was extracted from ' ~ ~ 3,5-dicaffeoyl-muco-quinicacid (210) was the roots of the grass B r ~ c h i a r i aand isolated from aerial parts of the Korean culinary vegetable Aster scaber. The latter exhibited potent inhibition of HIV-1 integrase (ICs0of 7 pg mL-').17' Quinic acid has been used as a starting material in the preparation of various enzyme inhibitors. Compounds 211 were made in multi-step syntheses as putative inositol monophosphatase inhibitor^.'^^ The phosphitamidites 212-214 were also made in lengthy reaction sequences from quinic acid and subsequently coupled to a 5'-O-unprotected cytidine derivative. Oxidation at phosphorus followed by deprotection gave e.g. phosphate diester 215 from 214. These donor substrate analogues proved to be good inhibitors of a-(2-.6)-sialyl transferases ( K j 10-4-10-5).173 The vicinal diol216, prepared in 10 steps from quinic acid, was elaborated into N-alkylated 2-epi-valienamines 217 in variable (16-98%) yield by reaction with Viehe's salt followed by Pd(0)-catalysed coupling with a range of primary (e.g. R' = H; R2 = Et, Bu, Hept, Oct, cyclohexyl, Bn) and secondary amines (e.g. R' = R2 = Bu, cyclohexyl, iPr).174Carbocyclic influenza neuraminidase inhibitors 219 ( n = 3 - 8 ) with a cyclic amine side-chain have also been prepared via Pd(0)-catalysed coupling of acetate 218 with the corresponding cyclic arnine~.'~' The use of pentafunctional quinic acid as a polyoxygenated scaffold for combinatorial synthesis has also been de~cribed.'~~ 2.7 Other Cyclitol Derivatives. - The distribution of products in the gas-phase acid-induced ring-opening with methanol, as well as condensed phase methanolysis, of cyclohexene oxides (e.g. 220) bearing remote O-functionality has been studied. Products and ratios varied widely depending on the reaction phase,
240
Carbohydrate Chemistry
the acid and in the case of gas-phase reaction, on the pressure Several polycyclic cyclitol derivatives have been reported. The decalinic compound 221 was synthesized from 3,4,6-tri-0-acetyl-~-glucal.As shown in Scheme 33, intramolecular Diels-Alder cycloaddition of the triene set up a tricyclic hex-5-enopyranoside derivative which underwent Ferrier rearrangent with mercuric sulfate and aqueous sulfuric acid to afford 221.'78Exhaustive osmylation of
OH OR OH
OR
OH
OBn
OAc 212
213
214
215
Et02C,
BnO
DJ3 /ACHN
X OHBOH n 216
OK NMe2
217
OAc 218
Me 221 Reagents: i, BF3.Et20;ii, NaOMe; iii, PivCl, pyr; iv, PDC; v, 155 OC; vi, HgS04, H2S04, H20, dioxane Scheme 33
241
18: Alditols and Cyclitols
tricyclic diene 222 was observed to give rise exclusively to the exo-hydroxylation product 223 in 66% yield. This compound was elaborated further to give, for example, the decahydronapht halene- 1,2,3,4,5,6,7,8-octa01224 which proved to be a selective and potent a-glucosidase i n h i b i t ~ r . ' ~ ~ D-Glucose-derived radical precursors 225 and 226 have been subjected to carbocyclization reactions to yield cyclic polyol derivatives in enantiomerically pure form. They underwent 6-exo-trig and 7-exo-dig radical cyclizations upon treatment with tributyltin hydride and AIBN to give the cyclo-hexitol and -heptitols, 227 and 228 respectively, in moderate yields."' Diastereoisomeric 'cyclooctanic carba-sugars' have been prepared in thirteen steps from D-glucose. The key step in the synthesis was a TIBAL-promoted Claisen rearrangement of the intermediate 2,6-anhydro-3,4,5-tri-O-benzyl-1,7,8trideoxy-~-ghco-octl,7-dienitol (Scheme 34) which created the cyclooctene ring. Hydroboration of the double bond with borane-THF followed by chain extension by oxidation, methylenation and a second hydroboration, gave rise to a separable mixture of cyclooctano carba-sugars with D-glyCerO-D-idO- and L-g lycero-D-ido-configurations."
6 Mh Meo
C14'
OMe
OH
& ,4,c
-
220
HO
222
223
OH HO'
OH
OH OH 224
OH
I
225 R = CH2 =CH2 226 R =
HO
3 -
k
-
,,
@
BnO
OBn
228
227
i __t
Reagents: Bu$Al, toluene, 50 "C
'-OBn
HOQoH
BnO
OBn
BnO
OBn
Scheme 34
References 1.
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18: Alditols and Cyclitols
247
164. M. Liu, J. Haddad, E. Azucena, L. P. Kotra, M. Kirzhner and S . Mobashery, J . Org. Chem., 2000,65,7422. 165. N. Nishizono and V. Nair, Nucleosides, Nucleotides, Nucleic Acids, 2000,19,283. 166. Y. Ding, E. E. Swayse, S. A. Hofstadler and R. H. Griffey, Tetrahedron Lett., 2000, 41,4049. 167. S. R. Kirk, N. W. Luedtke and Y. Tor, J . Am. Chem. Soc., 2000,122,980. 168. Y. Kobayashi, T. Ohgami, K. Ohtsuki and T. Tsuchiya, Carbohydr. Res., 2000,329, 325. 169. T. J. Baker, N. W. Luedtke, Y. Tor and M. Goodman, J . Org. Chem., 2000,65,9054. 170. P. Wenzl, A. L. Chaves, J. E. Mayer, I. M. Rao and M. G. Nair, Phytochemistry, 2000,55, 389. 171. H. C. Kwon, C. M. Jung, C. G. Shin, J. K. Lee, S. U. Choi, S. Y. Kim and K. R. Lee, Chem. Pharm. Bull., 2000,48,1796. 172. J. Schulz, M. W. Beaton and D. Gani, J . Chem. SOC.Perkin Trans. 1,2000,943. 173. C. Schaub, B. Miiller and R. R. Schmidt, Eur. J . Org. Chem., 2000,1745. 174. S . H. L. Kok and T.K. M. Shing, Tetrahedron Lett., 2000,41,6865. 175. W. Lew, H. Wu, X. Chen, B. J. Graves, P. A. Escarpe, H. L. MacArthur, D. B. Mendez and C. V. Kim, Bioorg. Med. Chem. Lett., 2000,10,1257. 176. C. W. Phoon and C. Abell, J . Comb. Chem., 2000,1,485 (Chem. Abstr., 2000,132,64 468). 177. F. Marianucci, G. Renzi, G. Amici and G. Roselli, Tetrahedron, 2000,56, 7513. 178. C. Taillefumier and Y. Chaplew, Can. J . Chem., 2000,78,708. 179. G. Mehta and S . S . Ramesh, Chem. Commun., 2000,2429. 180. J. Marco-Contelles and E. de Opazo, Tetrahedron Lett., 2000,41,5341. 181. W. Wang, Y. Zhang, M. Sollogoub and P. Sinay, Angew. Chem. Int. Ed. Engl., 2000, 39,2466.
19
Nucleosides
1
General
A review has discussed selective biocatalytic modifications of conventional nucleosides, carbocyclic nucleosides and C-nucleosides, including such topics as selective acylation of nucleosides, regioselective deacylation, and enzymic resolution of precursors of carbocyclic and C-nucleosides.' The enzymatic synthesis of antiviral nucleosides has also been reviewed, in Chinese.2A survey has been given of synthetic approaches to nucleosides in the unnatural L-series, and their potential use as antiviral and anticancer agent^.^ A review on the synthesis of deuterionucleosides discusses the synthesis of deuteriated sugars, particularly ribose and 2-deoxyribose,prior to attachment of the base, and also deuteriation at the nucleoside level. Both single-site and multiple-site deuteriation is ~ o v e r e d . ~ An account from Wengel's laboratory covers the synthesis of bicyclic nucleosides and their use in conformational restriction of resultant oligonucleotides. Structural types such as 3'-C, 5'-C-linked bicyclic nucleosides, as in bicycloDNA, and 2'-0,4'-C-linked systems, as in 'Locked Nucleic Acid' (LNA) are reviewed to the end of 1999.5 De Clercq has reviewed the use of guanosine analogues as anti-herpes agents. Although mostly acyclonucleosidesare covered, there are discussions of various types of carbocyclic nucleoside analogues, from cyclopropanes to cyclohexenyl compounds.6 A review has also appeared covering the synthesis of coenzyme A analogues and derivatives, and their applications as mechanistic probes of enzymes utilizing CoA esters.'
2
Synthesis
The synthesis of nucleoside analogues with high P-selectivity from glycofuranosyl chlorides has been reported. Thus, for example, reaction of the stable crystalline 1 with the appropriate base and KOBu' in DMSO gave the (3-nucleoside 2 almost entirely. The use of DMSO seems to be essential, and it CarbohydrateChemistry,Volume 34 0 The Royal Society of Chemistry,2003 248
249
19: Nucleosides
was speculated that an intermediate sulfonium species is involved. Although the process was not applied to S-D-ribofuranosyl nucleosides, several other cases were reported, such as the synthesis of 3 in 71% yield and with 32:l fJ-selectivity? OBn
I
0 0 Mex Me 1
0 Mex
OBn
0 2
Me
The D-erythrofuranosyl benzimidazole 4, various related 2-substituted analogues and some compounds additionally halogenated at C-4 have been prepared by base-sugar coupling. The enantiomer of 4 was also made, since the analogous L-ribofuranosyl compound has anti-HCMV activity. Some of the novel compounds also proved effective against HCMV? The ribavirin analogue 5 has been prepared by conventional coupling using the silylated base, and was converted to its 5’-triphosphate for use in studies of an engineered protein kinase that does not use ATP as phosphate donor.” In connection with studies of compounds with Type 1 cytokine-inducing activity, the L-enantiomer 6 of ribivirin has been prepared from L-ribose; the 2‘-deoxycompound was made from 6 by deoxygenation, and the 5’-deoxy-~-ribo-compound, L-xylo-ribavirin and its 3’-deoxy-derivative were also all made by basesugar condensation, with 6 displaying best potency.” The pyrimidinone 7 was prepared conventionally, for use in further chemistry (Section 13).12 Standard coupling (silylated base, ribofuranosyl acetate, TmsOTf) was used to prepare 8, convertible on ammonolysis to the 2-thiocytosine derivative 9. Similar methods were used to make pyranosyl compounds such as 11 (Ar = Ph, p-tolyl, 2naphthyl; D-galacto- and D-xyb-compounds also made),13but when condensations between salts of the bases and acetylated glycosyl bromides were used, the major products were bis-glycosylated compounds of type 10, produced together with the normal nucleoside derivatives.However, ammonolysis of 10 produced products of type 11 in high Standard coupling was used to prepare the 1-deazaadenosine derivative 12, convertible to compounds of type 13, used in studies of adenosine receptor binding.I5Various pyrrolo[2,3-dlpyrimidinone nucleosides have been prepared and evaluated for their ability to enhance Type 2 and suppress Type 1 cytokines in human T cells.16 The pyrido[2,3-d]pyrimidine nucleoside 14 has been prepared by base-sugar condensation; the 2’-deoxy-species was made by deoxygenation, the arabinofuranosyl analogue by a redox sequence on a derivative of 14, and the xylofuranosyl compound by base-sugar condensation. The compounds were studied for anticancer activity, 14 being the best proliferation inhibitor, but the xylo-compound had selective activity against cancer cells.” 1-Deazaguanosine (15) has been prepared by modification of AICA riboside.’* The trisubstituted indole nucleosides 16 (X = C1, Br) have been made as
250
Carbohydrate Chemistry 0
2NHBn N \ N.N
1c
I
P-D-Rib- f
OH OH 4
OBz OSz 7
OH OH 6 0
5
Ar
I
P-D-Rib-f
OAc OAc 8
10
9
yo2
OAc
YHR
P-D-Rib-f ( 0 A c ) ~ 12
p-D-’Rib- f
P-Dhib-f 13
. ’ p-Dh3ib-f 15
14
analogues of TCRB, and similar 2’-deoxy- and 2’,3’-didehydro-2’,3’-dideoxycompounds were also described, all having less activity against HCMV than does TCRB.I9There has been a further report on ‘stretched’tricyclic nucleosides related to TCRB, of type 17 (X = CH, Y = NHPr’, NHcyclopropyl, SBn, SH, C1) (see Vol. 32, p. 257), together with a range of similar analogues 17 (X = N) and the N3-ribosylated species (see also Vol. 33, p. 276-277).20
I P-D-Rib-f 16
CI‘ R
’ N
I
P-D-Rib-f 17
R
BzO 18
OBz 19
Br 20
Reaction of 1-amino-1-deoxy-D-fructose or its N-substituted derivatives with peracylated glycosyl isothiocyanates has led to condensation products of type 18. In the case of the ribofuranosyl compound subsequent treatment with acidic resin in ethanol gave the spironucleosides 19.21 The L-arabinofuranosyl nucleoside 20 has been prepared from L-arabinose. Also reported were the 2’-deoxycompound (L-BVDU), and both 2’-deoxy-2’fluoro-epimers.22
19: Nucleosides
25 1
1,2-Epoxideswere used as intermediates in the chemistry outlined in Scheme 1 for the formation of the differentially-protected P-D-xylofuranosylthymine 23 from the known tosylate 21 via the D-Zyxo-isomer 22.23 BnOCH2
AcOCH~
Ac0CH2
v,vi *
O @ + H:
Q 0 H . Z
Thy
Q
OTs OH 21 22 23 Reagents: i, NaOH, MeOH; ii, TsCI, py; iii, AcOH, Ac20, H2S04; iv, NH3, ether; v, KOBU’; vi, (Trn~)~Thy, CH2C12 Scheme 1
Cyclization of a D-glucopyranosylhydrazine derivative was used to prepare the 1,2,4-triazole nucleoside 24, and the analogous a-D-galactofuranosyl compound was synthesized similarly.24A range of l-P-D-xylopyranosylderivatives of 2-substituted-5-fluorouracils have been prepared by phase transfer catalysis or Koenigs-Knorr reactions.25
OAc 24
3
Anhydro- and Cyclo-nucleosides
Treatment of 9-(P-~-arabinofuranosyl)adenine(ara-A) with TPP and DEAD led in high yield to the D-lyxo-epoxide 25, whilst a similar reaction on adenosine gave the 2’,3’-0-triphenylpho~phorane.2~ The anhydronucleoside 26, in which the furanose ring is restricted to a 2‘-endo- (S-type) conformation, has been prepared by cyclization of a 1’-tosylate,and a 2,l’-anhydronucleoside, presumed to be an intermediate, could be isolated at shorter reaction times. The cytosine analogue of 26 was also made, and both products were devoid of anti-HIV activity in MT-4 cells.27 The 6,S-anhydronucleoside 27 was obtained by reaction of 2,3-0-isopropylidene-D-ribofuranosylamine with 3-isothiocyanatopropanal, and on treatment with aqueous acetic acid, 27 was converted to the 6,2’-anhydro-system 28. Crystal structures were reported for both 27 and 2!k2* The use of 1,l’-sulfonyldiimidazolehas been advocated for the synthesis of
wAde
HOCH2
25
0-
26
1’
OX0 Me Me 27
28
252
Carbohydrate Chemistry
anhydronucleosides, as for example in the preparation of the 2,3’-anhydrocompound 29 from 2’-deoxy-5’-O-Tbdms-uridine in over 90% yield.29Compounds of type 30 (R = Pri, CH2Pr’, CH2CH2Pr3have been obtained by base-catalysed cyclization of 3’-me~ylates.~’ When the 2,3’-anhydrothymidine derivative 31 was treated in DMF at 150 “C with either O,O-diethylphosphate or 0,O-diethylphosphorothioate anions, the isomeric N3-nucleoside 32 was obtained. It was speculated that the reaction proceeds by nucleophilic attack at C-1’ of 31, followed by recyclization. The structures of both 31 and 32 were determined by X-ray method^.^' The key step in a synthesis of cyclo-5,6-dihydro-2‘-deoxyuridine,a major product of gamma irradiation of deoxygenated aqueous solutions of deoxycytidine,is the cyclization of aldehyde 33 using Bu3SnHand AIBN, to give 34 of stereochemistry as indicated. The method was previously used for the thymidine analogue ( J . Chem. SOC.,Perkin Trans. 1,1999,1257). Both the uridine and thymidine analogues were incorporated into oligodeoxynucleotides, where they acted as blocks for DNA p~lymerases.~~ A number of examples of the use of anhydronucleosides as intermediates in syntheses of other types of analogue can be found elsewhere in this chapter. 0
0
31
4
29
32
0
30
OTbdps 33
OR
0
OTbdps 34
Deoxynucleosides
There has been a thorough account of work in Rizzo’s laboratory concerning the synthesis of deoxynucleosides by deoxygenation using photoinduced electron transfer, with carbazole derivatives as photosensitizers. In addition to the photolysis of 2’-m-(trifluoromethy1)benzoates to produce fJ-2’-deoxynucleosides (see Vol. 30, p. 272-273), the method has been employed for the selective removal of benzoyloxy groups, as in the formation of the cc-2’-deoxysystems36 (B = Ura, Thy, N-AcGua) by photolysis of esters 35 in aqueous isopropanol in the presence of 3,6-dimethyl-9-ethylcarbazoleand magnesium perchlorate, and for the synthesis of 3’-deoxy compounds 38 (B = Ura, Thy, Ade, N-AcGua) from precursors 37 under the same conditions. 2’,3’-Dideoxynucleosides40 (B = Ura, Thy, Hx) are also accessible by photolysis of the triesters 39 [Ar = m-(trifluor~rnethyl)phenyl]?~
253
19: Nucleosides
An alternative to Barton-McCombie deoxygenation, restricted to cases with an electronegative group, particularly fluorine, p- to the radical centre, involves the thermolysis of xanthates in diglyme, as in the conversion of 41 to 42. The reaction was thought to involve adventitious peroxides in the solvent, since their removal slowed the process considerably. Diglyme was found to be the hydrogen donor.34 A synthesis of 2’-deoxy-2-fluoroadenosine, a potential prodrug for 2-fluoroadenine, involves deoxygenation by reduction of the 2’-thiocarbonylimidazolide with (Tms)3SiHas hydrogen donor.35
w
OAc 35
Y Ar
0
39
37
0
Y Ar
6 40
OAc
38
OMe
OMe
0 4 10
/o
0
OBz OAc
Ar
O+Ar
0
OAc 36
T
SMe 41
42
A chemo-enzymatic approach has been used for the synthesis of thymidine specifically labelled with 13Cin the deoxyribose unit. Labels could be specifically placed at C-1’ or C-2’ starting from acetaldehyde labelled at C-1 or C-2 respectively, doubly-labelled acetate gave thymidine labelled at C-3’ and C-4, whilst 13C at C-5’ had its origin in [13C]dia~~methane.36 [~ugar-’~C~]Thymidine, additionally labelled stereoselectively with deuterium at C-2’ and C-5’, has been prepared from [13C6]glucose,via a selectively deuteriated ribose derivative prepared by stereocontrolled reductions. The labelled sugar unit could then be transferred to other bases using purine and pyrimidine nucleoside phosph~rylases.~’ Standard base-sugar linking procedures have been used to make the benzimidazole nucleoside 43, converted to the cross-linked bisnucleoside 44,38the pyrroles 45 (R = H, CONHS, which were made into triphosphates which exhibited a preference for incorporation into oligonucleotides with Klenow polymerasein place of either A or C,39and the pyrazoles 46 (X = OMe, NH2)and their 2’,3’-dideoxy-analogues.“O 6-Methylpurine-2’-deoxyribonucleosidehas been prepared by deoxygenation;l and, since the L-ribonucleoside has anti-HCMV activity, the L-2’deoxycompound 47 and some related amines have been made, again using radical deoxygenation, and 47 was found to be active.42The enantiomer of 47, and other related compounds such as the 2’-deoxyanalogue 48 of TCRB, have also been prepared, using either basesugar coupling or exchange of 5,6dichloroimidazole with the base of 2’-deoxyuridine, catalysed by N deoxyribofuranosyl transfera~e.4~ The 2’-deoxyanalogue 49 of tricyribine, made by base-sugar coupling, has been reported, along with the 3’- and 5’-deoxycompounds, prepared from toyocamycin. The 2’,3’-ribo-epoxide, the 2’,3’-
254
Carbohydrate Chemistry
TbdmsO
I
I
43
44 Ho
Ho 46
47
OH
Ho
Ho
45
48
dideoxycompound and d4 systems were also made from triciribine itself, all these analogues being less effective as antivirals or antiproliferatives.4 In connection with the synthesis of an RNA nonamer in both enantiomeric forms, in addition to the required L-ribonucleosides, L-2’-deoxythymidinewas also prepared, to act as an anchoring derivative in the synthesis, from ~-xylose.4~ The P-L-compound 50 (X = OH) has also been prepared from L-xylose, and was converted into the fluoro- and azido-analogues 50, (X = F, N3).46 5’-Deoxy-5-fluorocytidine has been prepared by base-sugar coupling, and used to make an orally-available prodrug of 5-fl~orouracil.4~ The 5-iodotubercidin analogues 51 (R = Me, vinyl, Et), and some related species, have been synthesized as potential adenosine kinase and the same group have also reported related 4-N-aryl-5-aryl-pyrrolo[2,3-d-JpyrimidinesP9
YN. N Me
H2N
HO
49
x
50
HO
OH 51
In the area of 2’,3’-didehydro-2’,3‘-dideoxycompounds (d4 systems), a previous method for their synthesis from 5’-protected 2’,3’-di-O-mesyl-nucleosides by treatment with arylselenyl anions (Vol. 3 1, p. 272) has now been modified by the use of bis(4-perfluorohexylphenyl) diselenide and sodium borohydride, which permits the use of the diselenide in catalytic quantities, and also its ready recovery. The method was used for the synthesis of d4-~ridine.~’ Analogues of d4T with potential linker arms at C-5, for attachment of either a fluorescent tag or a non-nucleoside reverse transcriptase inhibitor, have been prepared either from 5-(hydroxymethyl)uridine5’ or from the 2,2’-anhydronucleoside of 5(methoxycarbonylmethy1)uridine (Vol. 28, p. 265-266).52 Addition of iodine at C-2’ and C-3’ of protected pyrimidine nucleosides under Arbuzov reaction conditions has led to a new route to d4 sy~fems,5~ and d4-uridine has been prepared from 2’-deoxyuridine using elimination from the 3’,5’-dime~ylate.~~
255
19: Nucleosides
5
Halogenonucleosides
As part of an issue of Carbohydrate Research devoted to reviewing the whole area of fluorinated sugars, Pankiewicz has discussed nucleosides fluorinated in the sugar moiety, covering both synthesis and biological activity.55Another review has also covered recent strategies for the synthesis of fluoronucleosides, with some consideration of structure-activity relationship^.^^ Syntheses of the 2’-deoxy-2’-fluoronucleosides 52 have been carried out using the condensation of silylated 2,6-dichloropurine with 1,3,5-tri-O-benzoyl-2deoxy-2-fluoro-a-~-arabinofuranoseas a key step. Conformations of the nucleosides were analysed using the PSEUROT program, and they were incorporated into oligodeoxynucleotides which had practically the same affinity to both complementary DNA and RNA as did the parent unmodified The same sugar precursor was used in a synthesis of the fluorinated analogue 53 of TCRB, and the 3’-deoxy-3’-fluorocompound54 was prepared from TCRB itself, through tritylation to give mostly the 2’,5’-di-O-trityl compound, thus permitting introduction of fluorine at C-3’ with inversion of configuration. The analogues 55 (X = Br, NHPr‘) were made by a sequence involving enzymic sugar exchange between 2’-deoxy-2’-fluorouridine and 5,6-dichlorobenzimidazole.All these compounds had less antiviral activity and more toxicity than TCRB.58A method for the synthesis of 2‘,3’-dideoxy-2’- or 3‘-fluoronucleosides such as 42 was mentioned and some 3‘-amino-2’,3’-dideoxy-2’-fluoronucleosides are referred to in the next section. 2’,3’-Dideoxy-3’-fluoro-~-ribonucleosides56 (B = Cyt, Ura, Ade, Gua) have been prepared from D-glucitol, which was converted to methyl L-xylofuranoside, which was deoxygenated at C-2 prior to the introduction of fluorine at C-3 with inversion, and base-sugar coupling.59Other workers have also described the guanosine analogue (56, B = Gua) by a similar sequence, but with base-sugar coupling to an L-xylose derivative as an early stage.60 AdeIGua
OH
52
FJ c*lNy+Jcl
OH
/
CI
53
OH 54
OH F
WH20H 56 F
55
A procedure for the conversion of uridine to 5’-chloro-5’-deoxyuridinewithout the need for protection of 0-2’ or 0-3’ involves the treatment of the nucleoside with N-chlorodiisopropylamine and TPP, followed by hydrolysis of the resultant 5‘-chlorinated 2’,3’-0-triphenylphosphorane!l
6
Nucleosides with Nitrogen-substitutedSugars
Treatment of iodocompounds such as 57, made from furanoid glycals (Vol. 3 1, p. 269-270), with BuzSnO gives rise to anhydronucleosides such as 58 (Scheme 2), treatment of which with azide ion gave the 2’-azido-2’-deoxynucleoside 59. A
Carbohydrate Chemistry
256
better yield of 59 could be obtained by hydrolysis of 58 to the D-lyxonucleoside, followed by conversion to a triflate and azide
BnOCH2
Thy
57 I 58 Reagents: i, Bu2Sn0, DMF, 120°C; ii, NaN3, DMF Scheme 2
59 N3
A similar displacement of a 2’-triflate was used in the synthesis of amides such as 60, related to a known inhibitor of trypanosomal glyceraldehyde-3-phosphate dehydrogenase, from ara-A.632’-Amino-2’-deoxyuridinehas been linked through an amide to a coumarin; the resultant derivative was incorporated into oligonucleotides to act as a fluorescence energy donor to DNA.64 0
HMe
D
To10CH2 Urallhy
OBz
0 60
61 62 Reagents: i, NH3, MeOH; ii, Ph3P, DIAD, PhC02H Scheme 3
i“N 7’
pB
NPr’2 O-CH2
NHMmtr 63
The nucleosides 61 were formed with good p- stereoselectivity by condensation between the silylated bases and the a-glycosyl bromide. Conversion to cyclonucleosides 62 (Scheme 3) was followed by conversion to the arabinoconfigured 3’-amino-2’-fluoro-systems 63 (B = Ura, Thy, Cyt). These were incorporated into oligonucleotides linked by phosphoramidate bonds, and these were found to have high binding affinity to complementary nucleic acids (although not as high as for the corresponding 2’-ribo-fluoro-phosphoramidates; see Nucleic Acids Res., 1996,24, 2966), as well as greater acid stability than the non-fluorinated phosphoramidate-linked 01igomers.~’The same group has also reported the synthesis of the building block 64, made by base-sugar coupling, and a similar 2’-deoxycompound, made from AZT using chemical base exchange. These were incorporated into phosphoramidate-linked oligomers, which showed a considerable increase in stability for complexes with RNA or DNA, relative to adenosine-containing counterparts.66 AZT was used as a precursor to prepare a compound in which fluorescein was linked to the amino group of 3’-amino-3‘-deoxythymidine through a thioamide, a link resistant to enzymic degradation, and a spacer. The product was converted to its 5’-triphosphate for use as a chain terminator for DNA dye-terminator 3‘-Amino-3’-deoxythymidinehas been joined in hybrid structures, ~equencing.6~
257
19: Nucleosides
in which the two components are linked by urea units, to erythromycin (via its 9-amino-derivative) and azithromycin.68AZT has also been converted to the aminodiacid 65, and a similar structure was prepared from S-amino-5’deoxythymidine. These were incorporated into oligonucleotides at terminal positions, in an effort to preorganize high-affinity metal-binding Conjugates of nucleoside and non-nucleoside reverse transcriptase inhibitors have been prepared. These include species in which AZT is linked through spacers to the NNRTI via N3, or via a side-chain replacing the methyl group, and compounds involving ddC were also made. Some of the conjugates displayed antiHIV activity, but no synergistic effects were found.70 The L-enantiomer of 3’-azido-2’,3’-dideoxyguanosine has been prepared from L-xylose, but no significant antiviral activity was observed.60 Uridine has been converted in seven steps into 5’-amino-3’,5’-dideoxyuridine (66), related to the 4,5‘-unsaturated structure found in the mureidomycin antibiotic~.~’ Some 5’-Amino-5’-deoxy-5-iodo-pyrrolopyrimidine nucleosides such as 67 (X = Cl, NH2) have been prepared by sodium salt glycosylation procedures, and shown to be powerful adenosine kinase inhibitors!*
pN 1 A
PhOH2C
I
X
NH
OH 67 MmtrNH OTbdms 64
In connection with the synthesis of glucosamine-based oligonucleotide analogues (see Vol. 31, p. 293-295), a study was made of the regioselectivity of glycosylation of guanine derivatives with the acylated glucosamine 68. Use of 2-N-acetyl-6-O-diphenylcarbamoylguanine, which has been used with high N-9 selectivity in other cases, gave a mixture of regioisomers, and indeed only the N-7 isomer under some conditions. Use of 2-N-acetyl-6-O-benzylguanine, however, gave only the N-9 substituted product 69 in moderate yield.72Addition reactions of N-heterocycles to the nitrogalactal70 proceeded stereoselectivelyto give, after further manipulation, fl-D-galactosaminyl nucleosides such as 71.73Reaction of silylated thymine with di-0-acetyl-L-rhamnal gave a 2’-enopyranosyl nucleoside which could be converted to the AZT analogue 72.74
7
Thio- and Seleno-nucleosides
The 1’-phenylselenyl derivative 73 was obtained, but with only low diastereoselectivity,by reaction of the enolate with PhSeC1. Treatment of 73 with NaB& in the presence of CeC13gave stereoselective reduction to alcohol 74.75
258
Carbohydrate Chemistry OBn CH20Bn
68
NHCOCF3
”
69
\O
73
OH 74
Opening of 2,2’-anhydrouridine with 2-(Tms)ethanethiol gave the thioether 75, which could be converted to the methyldisulfide 76 by reaction with dimethyl(methy1thio)sulfonium tetraflu~roborate.~~ S-Hexyl-2‘-thiouridine has been synthesized, again by opening of a 2,2’-anhydro-system, and was incorporated into oligodeoxyribonucleotides, which had decreased duplex stability with both complementary RNA and DNA.77In an extension of earlier work (Vol. 33, p. 283), the P-D-ribo-thioglycoside 77 was converted under Mitsunobu conditions in the presence of 3-benzoylthymine into the a-D-arabinofuranosyl nucleoside 78 with good stereocontrol, whilst the a-D-arabino-compound 79 gave the P-D-ribonucleoside 80, again in good yield. Phenylselenyl glycosides behaved similarly.78 Reaction of a thiol with S-O-Dmtr-2,3’-anhydrothymidine was used to prepare S-(2-aminoethyl)-3‘-thiothymidine, which was converted to its S-triphosphate and coupled to an oxazine dye (see also ref. 67 above).79 CH20H
CH20H Tipds
OH S 75
Tms
79
OH S-SMe 76
OH
\O
77
80
78
OH 81
OH 82
A review has been given of the synthesis and biological activity of 4-thionucleosides, which also embraces oxathiolane analogues.8oThe 4’-thio-analogue 81 of ara-C has been prepared by base-sugar condensation, using a 4’-thioarabinofuranose building block previously used to make related purines (Vol. 32, p. 270), and was evaluated against human tumours, with ara-C proving generally more cytotoxic.81A range of 2’-deoxy-2’-fluorocompoundsof type 82, with both purine and pyrimidine bases, have been prepared by base-sugar condensations in which significant amounts of the a-anomers were also formed. In the pyrimidine series, a number of the 4’-thionucleosides showed potent anti-HSV
259
19: Nucleosides
activity, and the cytosine and 5-fluorocytosine derivatives had potent antitumour activity.82The (4-thio-~-arabinofuranosyl)-5-halopyrimidines 83 (X = F, C1, Br) have been prepared from a sugar unit accessible from ~ - x y l o s e . ~ ~
0
ON o-
SBn-
BnOH2C OBn 84 CH20H
83
BnOH2CO B n t
ill, iv
Y
OH 5-Et-Ura
85 Reagents: i, ICI, 2,6-di-Me-4-But-pyridine; ii, IC1, (Tm~)~-Ej-Et-Ura; iii, Bu3SnH,AIBN; iv, BBr3,DCM, -78 OC Scheme 4
The method of Scheme 4 has been developed for the synthesis of 2’-deoxy-4’thionucleosides. In the conversion of thioglycoside 84 to 85, a thiofuranoid 1,2-glycal was formed as an intermediate, and could be isolated, although the one-pot procedure, which gives good stereocontrol, was The same procedure could be applied to the formation of 86 (R = H, Et), although stereocontrol was poor, and a comparable amount of the alternative 1,2-transisomer was ~ b t a i n e d .The ~ ~ ?products ~~ 87 (X = C1, N3) could be obtained from 86, with 2,2’-anhydronucleosides as intermediate^?^ An alternative route to 2’-deoxy-4‘-thionucleosides developed in the same laboratory involves the synthesis of thioglycoside 88 from L-ascorbic acid (ascorbate carbons numbered) in a procedure (see Chapter 11) which compares favourably with an alternative approach to a similar compound (see Vol. 25, p. 138), and then linkage with the base with little stereocontrol. The p-anomer of 89 has good antiherpes activity.86 Some 4‘-thio-C-nucleosides are mentioned in Section 10, and a 4‘-thionucleoside antibiotic in Section 12.
4
OBn I 86
OH X 87
3
OBn 88
OH
89
5’-Acetylthio-2’,3’-O-isopropylideneadenosine has been made from isopropylideneadenosine by a Mitsunobu reaction, giving a route to 5’thioadenosine, and various S-alkylated derivatives such as the S-adenosylmethionine analogues 90 (R = NH2,C02H).87 The nucleosides 91 have been prepared by coupling of the silylated bases with the methyl glycoside of the selenoanhydrofuranoside (Chapter 1l), in the presence of TmsOTf.88
260
Carbohydrate Chemistry
OH OH 90
8
OH 91
Nucleosides with Branched-chain Sugars
The 2‘-deoxy-2’-methylene nucleoside 92 has been prepared using a Wittig reaction, and a number of other 4-amino-5-oxo-pyrido[2,3-d]pyrimidine ribonucleosides with chain branches at C-2’, C-3’ and C-4’ were also rep~rted.’~
93
92
94
Rhodium-catalysed carbenoid insertion has been used to make fused y-lactones, as in the conversion of diazoesters of type 93 into products 94 (R = H, COMe, C02Me), in which the indicated exo-isomer strongly p r e d ~ m i n a t e d . ~ ~ When the readily-accessible uridine derivative 95 is treated as indicated in Scheme 5,the lactone 96 is obtained, and this can be used to make nucleosides 97 containing other bases, either purines or pyrimidines.w
Tipds
-
Tipds
-
Tipds
95 96 Reagents: i, ( T ~ S ) ~ N(NH4)2S04; H, ii, base, HMDS, TmsCI, TmsOTf, MeCN Scheme 5
0
97
CH2C02H
The antitumour agent 2’-deoxy-2’-methylenecytidine has been conjugated (through the 4-amino-group) with folic acid, since the cell-surface folate receptor is overexpressed in some tumours and is therefore a target for drug delivery?’ Pyrimidine 2’-deoxynucleosides chain-branched at C-2’ have been prepared as outlined in Scheme 6. Slow addition of Bu3SnH and AIBN to 98 led to the formation of the product with a 2-hydroxyethyl group at C-2’ by rearrangement of the initially-formed radical prior to H-abstraction, but the yield was only A paper discussing 2’-deoxy-2’-substituted-l’,2’-unsaturated uridines is mentioned in the next section. A route to 2’,3’-dideoxy-2’-trifluoromethylpyrimidine nucleosides involves the synthesis of the lactone 99, and its separable cis-isomer, from isopropylidene-Dglyceraldehyde, which provides C-3 to C-5. Reduction of 99 and glycosylation gave, with moderate stereoselectivity,the nucleosides 100 (B = Ura, Thy, Cyt), and the cis-isomer of 99 could also be converted to 1’,2’-trans-nu~leosides?~ An alternative route to 100 (B = Ura) proceeds through the difluoromethylene
26 1
19: Nucleosides
D-
MmtrOCH2 ura
iii-v
i, ii
O, SePh Me. si J
Tbdmsb
\\
Me Me 98 Reagents: i, Bu3SnH,AIBN; ii, H202,KF, KHC03; iii, (Me3Sn)2,AIBN; iv, TBAF; v, TbdmsCl Scheme 6
compound 101, prepared using a Wittig-type reaction. Treatment of 101 with TBAF leads to the trifluoromethyl alkene 102, and a mechanism was proposed in which loss of ethylene from the Sem protecting group was followed by intramolecular delivery of fluoride to the difluoromethylene unit. Reduction and deprotection of 102 gave 100 (B = Ura). Similar chemistry starting from a 3’-keto-nucleoside gave the isomeric nucleoside 103 (B = U T ~ An ) . ~alternative ~ nucleosides has also been deroute to 3‘-deoxy-3’-trifluoromethylpyrimidine scribed, with the sugar unit 104, made from D-xylose (Chapter 14) as an intermediate. This was converted to nucleosides 105, and conventional radical deoxygenation was used to make the 2’-deoxycompounds 103 (B = Thy, Cyt). Elimination applied to a 2‘Gmesyl derivative was also used to give access to the alkene 106?5 DmtrOCH TbdmsOCH2
Hob ’,o
Qo
CF3 99
T;H2
C F3 100
b
BzOCH~
CF3 103
CF2
Me CF3 0104 Me
Tms 101 HOCH2 UralThy
DmtrOCH2
+
@ 102 cF3
k 9 CF3 OH 105
HOCH
CF3
106
2’,3’-endo-Met hylene nucleosides 107, involving all the main nucleobases, have been prepared in a stereoselective manner from isopropylidene-D-glyceraldehyde. The bases were introduced with stereocontrol using an a-glycosyl chloride. The enantiomers 108 were also made using similar chemistry, starting from L-gulono-y-lactone?6 A review on HIV-1 specific reverse transcriptase inhibitors has appeared, with Some new anaspecial emphasis on TSAO-T (109) and related logues of TSAO-T and its N3-methylderivative have been reported, with ethers and esters replacing the Tbdms group at 0-5’, and also with aminogroups at C-5’,and some of the ethers and amines had moderate activity?* A route to the 3’-carboxymethyl-3’-deoxyribonucleosides 110 (X = Nj, ODmtr) has been reported, in which the sugar unit is prepared from di-
262
Carbohydrate Chemistry
isopropylidene-a-D-glucofuranose, and the base is attached at a late A synthesis has been described in detail of the amide 111, together with its X-ray structure and that of the corresponding 5'-0-Tbdps carboxylic acid.'00Epoxycompounds of type 112 (X = NH2, NHOH, NHNH2) have been prepared through Darzens reactions on 3'-ketonucleosides. Ring opening of one such compound gave the chlorohydrin 113, and a similar reaction occurred with azide ion. Treatment of 112 (X = NHNH2, Ura series)with DBU in methanol gave the reduction product 114, a mechanism for the reaction being proposed."' The triphosphate of 3'-(2-aminoethyl)-3'-deoxythymidineand a similar compound with a longer spacer arm have been prepared, and linked through their aminogroups to an oxazine derivative, but these compounds failed as terminators in DNA sequencing.'023'-Deoxy-3'-hydroxymethyl-~-ribonucleosides of the main nucleobases have been prepared from L-xylose, but they did not show significant antiviral activity.lo3
"BY
TbdmsOCH2 H2wThy
wB"22"'""
HOCH2
108
107
HOCH2
TbdmsOCH2Urflhy
OTbdms
s-O 02
109
TbdmsOCH2 Urflhy
C p OH C02H 110 TbdmsOCH2 Qura
wcy2 y CONH2 111
0p
b
d 112
m
s
pCONH2 b d m s 113
c pC02Me OTbdms 114
The epoxide 115, made from (S)-glycidol, gave, on treatment with lithium hexamethyldisilazide, the furanoid glycal 116. This could be converted stereoselectively into nucleoside analogues of type 117, involving all the main nucleobases, by a sequence involving reductive removal of the sulfone, formation of an a-epoxide, and coupling of this with the appropriate base. In the pyrimidine series, related compounds in which the secondary alcohol was replaced with retention of configuration by fluoride and azide, or inverted, were made via anhydronucleoside intermediates, and the 2'-deoxycompound (B = Ura) was made by convertional radical deo~ygenation.~'~ Both anomers of 118 were made, as racemates, by base'sugar' linkage.'05 The C-vinyl compound 119 was converted, by hydroxylation, base-catalysed cyclization, coupling to silylated thymine, and debenzylation, into the tricyclic nucleoside 120.'06 A range of nucleosides 121 have been prepared by base-sugar coupling, with the quaternary carbon being established by chirality transfer using a Claisen rearrangement of an intermediate derived from isopropylidene-~-glyceraldehyde.'~~ Radical cyclization of 122 gave the 3'-methylene nucleoside 123, as well as the product 124 of 1,6-H transfer derived from the other diastereoisomer of 122."' Some references mentioning 3'-branched nucleosides are discussed in Section 14 below. Some new 3'- and 4'Gbranched compounds have been made and incorporated into oligonucleotides 125 (X = H, OMe) and 126 (X = F, OMe). The
263
19: Nucleosides
S02Ph 115
Ph02S'
GThY
I
0 118
OH 117
116 r O
OBn OMS 119
Me 121
OH 120
-
122
UraNMe
n
123
124
presence of units 126 increased affinity towards complementary RNA and DNA, whilst the systems 125 led to duplexes of unchanged or lower ~tabi1ity.l'~ A report from Matsuda's laboratory has described the preparation of 4'a-C-(2aminoethy1)thymidineand its incorporation into oligodeoxynucleotides which were significantly resistant to snake venom phosphodiesterase and endonuclease."' Compounds in which the aminoethyl group is linked to a lipophilic group such as a fatty acid have also been made and incorporated into oligodeoxynucleotides,with a view to increasing membrane permeability."' \
\
H2N I
o=p-oI 125
? x
o=p-oI
126
H(P OH
127
There has been a further report (see Vol. 33, p. 292) on the preparation of 4-C-alkynyl-2'-deoxynucleosides127, including cases with both purine and pyrimidine bases, and, in the pyrimidine series, arabinofuranosyl nucleosides were also prepared through anhydronucleoside intermediates. Some of these compounds had good anti-HIV activity.'12 Interest continues in conformationally-locked bicyclic nucleosides and their oligomers. A report from Wengel's laboratory describes details of the synthesis of the c~-L-LNA(locked nucleic acid) nucleoside 129, in which a key step is the treatment of ditosylate 128 with NaOH in aqueous ethanol to establish the bicycle, a reaction thought to involve a 2,2'-anhydronucleoside as an intermediate. Also reported is the similar conversion of 130 into the c~-L-x~Eo-LNA nucleoside 131.'13The effect on RNA binding of the incorporation of these two compounds, and the previously-prepared P-D-xylo-isomer and LNA nucleoside itself, into oligonucleotides has been studied; the behaviour of the other four stereoisomers of LNA, enantiomeric with those synthesized, was also studied
264
Carbohydrate Chemistry
indirectly by using ent-RNA, derived from L-ribonucleosides. Increased binding efficienciestowards RNA, as compared to the DNA reference, was found for six of the eight stereoisomeric LNAs, and particularly strong binding was found for LNA itself and WL-LNA, the oligomer of 129.’14Full details have been given of the synthesis of the abasic LNA monomer 132 (Vol. 33, p. 292), and the synthesis of the ring-cleaved analogues 133(X = OH, H) were made by adaption of earlier chemistry. On incorporation into oligomers, 132 had similar effects to a normal abasic nucleoside, whereas the monocyclic species 133 caused destabilization of duplexes.’l 5 The structures of LNA:RNA duplexes have been studied by NMR; it was found that the introduction of three modified units induces major conformational changes in the remaining unmodified units in the DNA strand, changing all except the terminal ones to N-type conformations, and leading to speculation as to how to tune an LNA:RNA duplex so that it would become a substrate for RNAse H.’l6 Imanishi and co-workers have shown that one LNA modification in a pyrimidine deoxyoligonucleotide could promote triplex formation with a DNA duplex in a highly sequence-selective manner.’17 A further synthesis of the 2’-0-,4’-C-methylene analogue of AZT has been reported (see Vol. 33, p. 292-293), and the a-L-xylo-compound 134 was also prepared, using a trimesylate analogous to 130 as precursor. Neither compound displayed antiHIV activity.’l8 Some related C-nucleosides are mentioned in Section 10. TsOCH~ Thy
Q
DrntrOCH;! OTs 128 CH20H
132
9
Mso OBn OMS 129 130 & T h Y H 0 p J
133
131
134
Nucleosides of Unsaturated Sugars and Dialdoses
As in earlier volumes, 2’,3’-didehydro-2’,3’-dideoxynucleosides (d4 compounds) are discussed with their saturated counterparts in Section 4. There has been a full account of the synthesis of the 2’-stannylated alkene 135 (X = SnBu3)by base-induced stannyl migration from C-6 (see Vol. 32, p. 275), and the application of this compound to the preparation of the alkenyl halides 135(X = C1, Br, I), and products with carbon substituents at C-2’ through Stille couplings.i19Reaction of di-0-acetyl-L-rhamnal with silylated thymine gave the 2’-enopyranosyl nucleoside by allylic rearrangement, as a mixture of an0me1-s.~~ A paper discussing a glycal substituted at C-3 with a nucleobase is mentioned in Chapter 10, and a 3’-ene derived from thymidine is mentioned in Section 17. The bromoalkene 136 is produced stereoselectively when the corresponding
19: Nucleosides
265
Tbdrnsb
OTbdps 136
135
OH OH 137
gem-dibromide is reduced with dimethyl phosphite and triethylamine.l2OThe doubly-homologated dibromoalkene 137 has been prepared by coupling adenine to a sugar unit prepared (Chapter 2) from di-isopropylideneglucose.Treatment of 137 with BuLi gave the corresponding 6'-alkyne, and the gem-bromofluoride was also reported. The effect of these compounds on S-adenosylhomocysteine hydrolase was studied, with time- and concentration-dependent inactivation being observed, as well as partial reduction of the enzyme-bound NAD+.121Some related alkynyl nucleosides are mentioned in Section 17. In further investigations of transglycosidic tethers for conformational restriction of pyrimidine nucleosides, it has been found that 6-formyluridine-5'-carboxaldehyde exists in aqueous solution as the bis-hydrate 138, whereas the isopropylidene derivative of 6-formyluridine-5'-carboxaldehyde formed the bridged spiro-fused system 139 (X = OH), the structure of which has been previously confirmed by X-ray crystallography (Vol. 29, p. 335). The isopropylidene derivative of 6-(hydroxymethyl)uridine-5'-carboxaldehyde also cyclized to give 139 (X = H), whilst once again the compound without the isopropylidene group showed no tendency to form a transannular link.'22 0
OH OH 138
10
0
0 0 MeX Me 139
C-Nucleosides
The oxadiazole 140, related to ribavirin, has been prepared by cyclization of a known sugar-protected amid0~ime.l~~ The 4-thio-analogues 141 (X = 0, S) of furanfurin and thiophenfurin (Vol. 29, p. 283), themselves analogues of ribavirin, have been prepared by condensation between the heterocycles, as their ethyl esters, with O-protected derivatives of 4'-thioribofuranosyl acetate. The thiophene compound ('thiophenthiofurin') had cytotoxicity towards cancer cell lines, but less so than thi0phenf~rin.l~~ A previously-known 2,5-anhydroglucose derivative 142 has been converted to the pyrazole 143, and some related comp o u n d ~ .Some ' ~ ~ pyrazole iso-C-nucleosidesare mentioned in Chapter 2. Various 3-cyano-2-(p-~-ribofuranosyl)-1,5-benzodiazepines have been prepared by a novel ring transformation of 5-(tri-O-benzoyl-~-~-ribofuranosyl)isoxazole-4carbaldeh yde.' 26
266
Carbohydrate Chemistry CONH? N Oi YNC O N H 2
HOcf
MSocPnO
OH OH 141
P-D-Rib-f 140
~
OH 142
HX$
CONH2
OH NHBz 143
A range of 2'-deoxypyrimidinyl-C-nucleosides144 have been prepared by parallel synthesis from acetylenic ketones and amidines; the anomers could be obtained as separated isomers, although anomerization had occurred during the pyrimidine-formingstep.lZ7The pyrimidinyl C-nucleoside 145 has been prepared to a furanoid glycal as using Pd-catalysed coupling of 2-amino-5-iodopyrimidine a key step. It was incorporated into oligonucleotides, as was a related pyridine C-nucleoside, for use in studies of base-triplet formation involving C-G and G-C base pairs.12' The 1,2,3-triazole 146, and the a-anomer, have been prepared by cyclization of acylic precursors.' 29 Conformationally-locked C-nucleosides such as 147 have been reported from Imanishi's laboratory. These were prepared by formation of the C-1'-0 bond in Mitsunobu reactions, the necessary diols being formed by stereoselective addition of Grignard derivatives of the heterocycles to an aldehyde. Use of lithiated heterocycles gave substantially more of the other epimers of the diols, thus permitting access to the a-anomers after Mitsunobu rea~ti0n.l~' The oxazole 147 and the compound without the phenyl group were incorporated into oligonucleotides, and the triplex-forming ability of the these towards a purine sequence of duplex DNA was ~tudied.'~' Me
NIPh N
OH
144
OH
145
OH 146
147
The aza-C-nucleosides 149 (X = H, NHz) are potent inhibitors of purine nucleoside phosphorylase. These compounds, termed 'immucillins', have been prepared from the acetonitrile derivative 148, which could itself be made by addition of lithiated acetonitrile to the cyclic imine. Various 5'-deoxy-, 5'-deoxy5'-flUOrO-, and 2'-deoxy-analogues were also prepared.'32 11
CarbocyclicNucleosides
A review has appeared covering the chemistry of carbocyclic nucleosides published over the period 1994-1998, discussing compounds with ring sizes from three to six, and also bicyclic
267
19: Nucleosides TbdmsOCH2
0
0 OH OH 149
M e X Me 148
A report has discussed at length work carried out in Trost's laboratory on the synthesis of carbocyclic nucleosides such as carbovir (150) and abacavir (151) from cis-3,5-dibenzoyloxycyclopent-2-ene, using Pd(0)-catalysedintroduction of the nucleobase and a precursor of the hydroxymethyl group, and introducing asymmetry by the use of chiral ligands on palladium (see Vol. 26, p. 247). The work was extended to the synthesis of 2',3'-dihydroxylated compounds, including (-)-aristeromycin and (-)-neplanocin A (see Vol. 31, p. 261).134In an alternative approach to the same compounds, the syn-aldol product 152 was converted using Grubbs' catalyst into the cyclopentene 153, and Pd(0) chemistry was again used to attach the base units in syntheses of carbovir (150) and abacavir (151).13'A similar approach using olefin metathesis was also used in a synthesis of carbocyclic ribavirin (154)but, due to a low yield in the step in which the base (as its ethyl ester) was linked to a 1',2'-epoxide, a more linear sequence in which the heterocycle was assembled stepwise, and with enantiopure 2-azabicycloC2.2.1Jhept-5-en-3-one as starting material, proved more satisfactory. Linkage of the intact base unit to a different carbocyclic synthon gave a route to the N2-linked analogue of 154.136
spy 4 N H
H"" ca
CH20H 150
N'
151
CYCONH2
0
ynj 152
0
OH -
O
?
0 "
p
Bn153 HO
HOCH2
Q,
N-N2
OH OH 154
11
150,151
Enantiopure 2-azabicyclo[2.2.l]hept-5-en-3-one has also been used as starting material in an efficient synthesis of abacavir (151), amenable to large-scale p r o d ~ c t i o n . Carbocyclic '~~ 5'-norcytidine (156), which showed activity against the Epstein-Barr virus, has been prepared, with the alkene 155 as the immediate precursor. The enantiomers of both of these compounds were also de~cribed.'~' The uridine analogues of 155 and 156, and their enantiomers, have also been prepared, using Pd(0)-catalysed coupling of the sodium salt of uracil with enantiopure allylic acetates.'39A paper describing a route to either enantiomer of a hydroxylated cyclopentylamine useful for making carbocyclic nucleosides is mentioned in Chapter 18. Racemic homocarbovir (157) has been prepared from n ~ r b o r n a d i e n e , ' ~and , ' ~ ~the analogue 158 of carbovir, and the related abacavir derivative, have also been synthesized as racemates, starting from cyclopentadiene.142
a
268 “0 “
OH
-
cfl
Carbohydrate Chemistry OH & )a
OH OH 156
155
H
CHsOH O W
-
-
157
158
(-)-Carvone was used as a precursor for the synthesis of the cyclohexene 159, and this was used to make the cyclohexenyl nucleoside analogue 160. The same chiral precursor was also manipulated to give the enantiomers of 159 and 160. Both enantiomers of 160 showed potent antiherpetic activity. Molecular modelling of the binding of both compounds to the active site of HSV-1 thymidine kinase was carried out, and a model for the binding of both enantiomers was proposed. 143 An analogue of carbocyclic 2’-deoxyuridine, conformationally-restricted due to a 6,6-oxido-link (Vol. 32, p. 278), has now been reported in optically-active form, in the L-series.14 An intermediate prepared from isopropylidene-D-glyceraldehyde via a Claisen rearrangement and previously used for the synthesis of some branched-chain fluorinated nucleosides (Vol. 32, p. 272-273), has now been used to make a fluorinated cyclopentane unit, to which was linked 6-chloropurine, thus leading to carbocyclic 2’,3’-dideoxy-4’-fluoro-~-adenosine (161).’45The same synthetic sequence could be modified to generate, via a metathesis step, an enantiomeric cyclopentane unit, and hence the enantiomer of 161, and equivalent structures with the other n~cleobases.’~~ There has been a further report on the synthesis of racemic 2’,3’-dideoxy-2’,3’methanoadenosine (see Vol. 33, p. 297).’474’-Hydroxymethyl-carbocyclicnucleosides 162 (B == Ade, Thy) have been made as racemates, along with their 3’-e~imers,’~~ and the compounds 163 (B = Ade, Hx) have been described.’49 References to the carbocyclic analogues of oxanosine and oxetanocin are mentioned in the next section.
OTbdms 159
12
OH
160
161
OH
162
163
Nucleoside Antibiotics
Oxanosine (164, X = 0)has been converted into its 2’-deoxy-, 2’,3’-dideoxy-and 2’,3’-didehydro-2’,3’-dideoxy-analogues, and into its 5’-monophosphate, by conventional manipulations. The carbocyclic analogue 164 (X = CH2)of oxanosine was also prepared from ( -)-2-azabicyclo[2.2.1] hept-5-en-3-one, and, by variations on this route, the 2’,3’-dideoxy- and 2’,3’-didehydro-T,3’-dideoxy-~ompounds were synthe~ized.’~~ Derivatives of bredinin (165) have been prepared, in which the antibiotic is deoxygenated, phosphorylated or carbamoylated at 0-5’. To make these it was necessary to carry out a photochemical ring opening of the isopropylidene derivative of bredinin, giving 166, on which the modifications could be performed, followed by reformation of the imidazole ring.’51 A synthesis has been reported of phosmidosine A (167), the N-acylphos-
269
19: Nucleosides
piloramidate being assembled by reaction of a 5'-phosphoramidite of 8oxoadenosine with prolinamide, protected at the ring nitrogen with the baselabile 4,4',4"-tris(benzoy1oxy)trityl group, followed by oxidation at phosphorus and deprotection under non-acidic condition^.'^^ The glycosylated uridine 168 has been prepared, using Crich's procedure for making P-mannosides (Vol. 30, p. 18). This compound is an analogue of tunicamycin, in which the disaccharide mimics the undecose tunicamine in the antibiotic, and which is capable of orthogonal derivatization on the L-mannose unit at positions corresponding to further units of the tunicamycin structure, with a view to producing analogues with more selective bioactivity. The analogue 169, incorporating a fatty acid chain similar to that in tunicamycin, was made from 168.'53
HoB*" BocNHP O N H 2
OH OH 164
n
OH OH 165
B0
HO
BnO BnO
OH OH 167
168 R = CH20Bn
W HO
O HO
169
-
Bra OH OH
Ribosylation of isopropylideneuridine and subsequent manipulations led to the synthesis of 170 (R = H), which constitutes a part-structure of the liposidomycin class of antibiotics. The two isomers of 170 (R = CH20H)were also prepared in synthetic sequences that involved ribosylation of D-allofuranose and L-talofuranose derivatives at 0-5, with introduction of uracil at a late stage. Molecular modelling was carried out of both liposidomycins and tunicamycin with the UDP-N-acetylmuramic acid-pentapeptide that is the substrate for the enzyme (translocase) in bacterial cell wall biosynthesis that the antibiotics inhibit, and, in accordance with the predictions, only the S-isomer of 170 (R = CH20H)was a good i11hibit0r.l~~ A number of nikkomycin analogues of type 171 have been prepared by acylation of uracil polyoxin C with aminoacid units, using N-hydroxysuccinimidyl esters as intermediates. The best inhibitory activity against fungal chitin synthase was found for cases in which the aminoacid was an S-arylmethyl derivative of L-cysteine or peni~illamine.'~~ The final stages in the biosynthesis of the peptidyl-nucleoside antifungal agent blasticidin S , produced by Streptornyces griseochrornogenes, have been eluci-
270
Carbohydrate Chemistry
dated. The organism exports blasticidin S in the form of an N-leucyl derivative as a self-protective mechani~rn.'~~
170
171
172
A new synthesis of the inositol 1,4,5-trisphosphate receptor agonist adenophostin A (172) has been reported, in which a suitably-protected adenosine is linked to a glucosyl 1-phosphite in an a-selective coupling, and where the manipulation between the coupled product and the final target 172 was minim i ~ e d . ' ~ ~The , ~ ' 'method was also applied to the synthesis of analogues in which the glucose bisphosphate unit is replaced by either a D-mannose bisphosphate or a D-xylose bi~phosphate.'~'A synthetic approach in which attachment of the base is a late step was used to make the adenophostin analogues with the adenine unit replaced by either an imidazole ring or purine itself (i.e.lacking the 6-aminogroup). This latter analogue had similar potency to adenophostin A, whilst the imidazole derivative was approximately equipotent with inositol 1,4,5-trisphoshate.'^^ A similar synthetic approach has been used to prepare the 5'-amino-5'deoxy-analogue of adenophostin A, which was then linked as an amide to a benzophenone derivative to give an adenophostin derivative with an attached photoaffinity label. Another photoaffinity derivative was also prepared, in which the benzophenone was linked via a tether as an aglycone replacing the adenine unit Staurosporine (173) has been converted to the 4',5'-alkene via amine oxide pyrolysis; the alkene was hydroxylated, and also subjected to hydroboration-oxidation to give regioselectively the 5'-a-alcohol. Various other subsequent manipulations at the 4'- and 5'-positions were also reported.I6l 4 - N Methyl-5'-hydroxystaurosporine and 5'-hydroxystaurosporine are new indolocarbazoles that have been isolated from a marine Micromonospora strain.'62 In the area of carbocyclic nucleoside antibiotics, a full account of syntheses of (-)-aristeromycin and (-)-neplanocin A (see Vol. 31, p. 261) was mentioned above.134The known intermediate 174, prepared from D-ribose, has been used for the first synthesis of neplanocin C (175), a minor component of the neplanocin family. The diastereomeric epoxide was also ~ b t a i n e d . In ' ~ ~efforts to prepare prodrugs, the oxetanocin analogue 176, an antiviral agent (lobucavir), has been selectively aminoacylated with L-valine on either of the hydroxymethyl groups using enzymic methods.'64A synthesis of the cyclohexenyl nucleoside antibiotic pyralomycin l c is mentioned in Chapter 18. An inhibitor of seryl t-RNA synthetase, SB-217452, isolated from a Streptomyces species, has been identified as the 4'-thionucleoside 177. The nucleoside moiety seems to be identical to one obtained as an enzymic cleavage product of albomycin 62 (Vol. 18, p. 182).'65 A paper on the total synthesis of spicamycin aminonucleoside is mentioned in Chapter 10.
27 1
19: Nucleosides
...- . .. .
173
" O V u a CH20H 176
13
174
175
H2N-
177
oH
Nucleoside Phosphates and Phosphonates
13.1 Nucleoside Mono- and Di-phosphates, Related Phosphonates and Other Analogues. - The reagent 178 has been developed for the phosphorylation of the 3'- or 5'-hydroxy-groups of otherwise-protected deoxynucleosides. The reagent incorporates a Dmtr group to help monitor the progress of phosphorylation, and the nucleoside phosphate is produced by treatment of the initial phosphodiester with NaOH in pyridin-thanol, which can be done during work-up of the reaction.166 A route has been developed for the synthesis of ribonucleoside 2'-phosphates 179, which could be incorporated into oligonucleotides. The t-butyl esters could be removed under mild acidic conditions without cleavage of internucleotidic links.167 The mesylate 180, the synthesis of which from the tertiary alcohol required the preparation of the sulfinate followed by oxidation, gave 181 on treatment with TBAF, by an unusual phosphonate-to-phosphate rearrangement of unknown mechanisrn.l6*
Triesters of type 182 (n = 2-5) have been prepared from the nucleoside 3'-H-phosphonate, via the cyclic phosphites. Methods were also developed for making H-phosphonates and phosphodiesters involvingjust one of the hydroxygroups of the di01s.l~~ A report from Stec's laboratory describes the preparation and separation of the diastereoisomers of triethylammonium 5'-O-Tbdms-thymidine 3'-O-methanephosphonothioate, and their reaction with p-nitrophenylsulfenyl chloride to
272
Carbohydrate Chemistry
give the disulfide 183. Treatment of 183 with TPP gave the pyrophosphonate derivative 184, whereas the use of TPP in the presence of excess p-nitrophenylsulfenyl chloride gave the methanephosphonodithioate 185 in a stereospecific manner.I7’ S-Phenyl methanephosphonothioates 186, the diastereomers of which can be separated, have been prepared by reaction of the protected nucleosides with methanephosphonyl dichloride, followed by thiophenol. They could be used for the preparation of methanephosphonyl dinucleotides, but the procedure did not prove to be 0ptima1.I~~ Procedures have been developed for the conversion of nucleoside 3’-H-phosphonate monoesters into H-phosphonothioates 187 (X = 0)or H-phosphonodithioates 187 (X = S) by reaction of aryl diesters of bis(ary1) phosphites respectively with 1,1,1,3,3,3,-hexamethyldisilathiane.’72
v
DmtrOCH2
v
DmtrOCH;!
o\pl’p
PhS’ ‘Me 186
tY
DmtrOCH2
187 R = H, OTbdms
2’-Deoxynucleoside3’-C-phosphonates188have been prepared by reaction of 3’-ketonucleosides with tris(Tms) phosphite. Some of the chemistry of these geminal hydroxyphosphonates was also exp10red.l~~ 3’-Methylene-H-phosphonates 189 [X = H, OMe, F, O(CH2)20Me),and also 5’-O-Dmtr species of use for oligonucleotidesynthesisby the H-phosphonate method, have been prepared by reaction of iodomethylene compounds with bis(trimethylsilyoxy)phosphine.’74 GMP has been prepared from guanosine by an enzymic method,17’ and an improved synthesis of guanosine 5’-monothiophosphate from 2’,3’-0-isopropylideneguanosine, which avoids the need for chromatography, has been de~cribed.”~ The pyrimidinone 7 has been converted into the 5’-phosphate 190, for use in studies of covalently-linked base pairs.’*Nucleotide libraries of type 191 (X = 0, S) have been assembled using solid-phase technique^.'^^ The uridine-derived 5’-oxyphosphorane 191a has been prepared from the 5’-phosphite and o-~hloranil.’~~ A range of deoxyadenosine bisphosphates with modified ribose units have been prepared and evaluated as ligands at the P2Y1receptor. The modications included deoxy-compounds,carbocyclic analogues, anhydrohexitol nucleosides, and morpholino-compounds.’79Improved routes have been reported to the
273
19: Nucleosides OH 0
3’,5’-bisphosphatesof 4-thiouridine, 6-thioinosine and 6-thioguanosine, for use as donor molecules in RNA ligation.”’ An extensive paper from Sekine’s laboratory has discussed the synthesis of aminoacylamido-derivatives of AMP (192),analogues of aminoacyl adenylates. The syntheses, which were successfully completed using a number of a-amino acids, used as a key step the reaction of 5’-0-phosphoramidite derivatives of adenosine with the amides of the suitably-protected amino acid.I8’The application of similar chemistry in the synthesis of phosmidosine was mentioned above.”* 2 ’ 4 45-U-Phosphoryl-~-~-ribofuranosyl)adenosine has been prepared from a previously-described ribosylated adenosine (Vol. 31, p. 296).182 There have been further reports on potential prodrugs of AZT and its monophosphate. Phosphoramidates 193 (X = Y = 0) have been prepared using H-phosphonate chemi~try,’~~ and both phosphoramidothioates 193 (X = S, Y = 0)and phosphoramidodithioates 193 (X = Y = S), with phenylalanine and tryptophan as amino acids, have been synthesized using 1,3,2-oxathia- or dithia-phospholane chemistry.ls4S-Acyl-2-thioethylaryl phosphotriester derivatives of AZT have been prepared as mononucIeotide prodrugs. They acted as such in thymidine kinase-deficient cells, and it was proposed that activation involves successive esterase and phosphodiesterase hydrolysi~.’~~ H-Phosphonate diesters 194 have been prepared; esters of primary or secondary alcohols were degraded in serum or phosphate buffer to give AZT, whereas esters of tertiary alcohols gave AZT-5’-hydrogenphosphonate. Similarfindings were reported for ddA and d4T.lS6
192
193
194
The novel 5-fluoro-2’-deoxyuridinephosphoramidate prodrug 195 has been prepared, along with the compound with only one bromoethyl group. The
274
Carbohydrate Chemistry
mechanism of conversion of 195 to FdUMP was thought to be via aziridinium species, after initial hydrolysis of the N-hydroxybenzotriazolyl The mechanism of hydrolysis of some related thymidine-derived phosphoramidates was investigated, with aziridinium intermediates being involved in the case of N-(2-bromoethyl) compounds, whilst a piperidino-group on phosphorus was hydrolysed by an endogenous phosphoramidase.’88Some 5’-phosphodiesters of 1-(~-~-arabinofuranosyl)-2-thiocytosine and a long-chain alkanol were synthesized and evaluated in vivo as antitumour agents, with some compounds showing promising ~ r 0 p e r t i e s . l ~ ~ 5’-Vinylphosphonates of cytosine, uracil and ara-C have been prepared by Wittig reactions, and intermediates in these syntheses were hydroxylated using AD-mix-a to give the product 196 and the related derivatives of uridine and cytosine.190Geminal hydroxyphosphonates 197 (R = Me or H, and with all four nucleobases) have been prepared by addition of dimethyl phosphite or tris-Tms phosphite to 5’-aldehydes. Similar products were obtained from 2’,3’-0-isopropylidene ribonucleosides, except in the case of adenosine. NMR studies indicated that the major diastereoisomer formed in each case had 5‘-Rstereochemistry, and in some cases this was produced in up to 90% d.e.19’ The 5’-(Pa-boranodiphosphate)analogues 198 of ADP and GDP have been prepared, by reaction of 2’,3’-di-0-acetyl-5’-phosphoramidites with the borane complex of Hunig’s base, followed by deacetylation and coupling with phosphate. The diastereoisomers were separable by RP-HPLC. The products, more lipophilic than the diphosphates and resistant to nucleases, could have application in boron neutron-capture therapy.’92 0
0
Br
195
196
197
198
13.2 Cyclic Monophosphates and Their Analogues. - A new preparative route to cyclic phosphorothioates of type 199 involves the reaction of 5’-O-Dmtr-nucleosides with diphenyl H-phosphonate in the presence of pyridine, followed by treatment of the resultant cyclic H-phosphonates with sulfur and final deprotection with acetic acid. The method was used with all four ribonucleobases, and gave the products as 1:l mixtures of diastere~isomers.’~~ The phosphinic acid analogue 200 of cyclic AMP has been prepared by linking adenine to a cyclic methyl phosphinate derived from di-o-isopropylideneglucose (Chapter 17).’94Thymidine cyclic 3’,5’-phosphorofluoridateand its sulfur analogue (201, X = 0 or S), as 1:l mixtures of diastereomers, have been prepared by oxidation or sulfurization of the cyclic phosphor~fluoridite.’~~ 7-Deoxypaclitaxel has been linked to cyclic AMP as a phosphotriester; the product showed enhanced cytotoxicity against human cancer cells.’96
19: Nucleosides
275
13.3 Nucleoside Triphosphates and Their Analogues. - A review has been given of the most useful methods for the synthesis of nucleoside triph~sphates.’~’ 5’Triphosphates of 8-(alky1thio)adenosines have been prepared as inhibitors of nucleoside triphosphate diphosph~hydrolase,’~~ and the triphosphates 202 and that derived from 2,2’-anhydrouridine have been made as agonists for P2Xzpurinoceptors, but they showed lesser potencies than the parent n~cleosides.’~~ Derivatives of ATP, UTP and CTP have been prepared in which methyl ketone groups are attached via spacers to the base units, in order to permit interaction with fluorescent probes after enzymic incorporation into oligonucleotides. The triphosphate was assembed by Eckstein’s procedure, in which a 2’,3’-0-isopropylidene nucleoside is treated sequentially with salicyl phosphorochloridite, pyrophosphate and an oxidant.200 Reduction of ATP to the 2’-deoxy-compound has been carried out on a preparative scale using recombinant Lactobacillus leichmannii ribonucleotide triphosphate reductase.20’ The 3‘-0-phosphonomethyl compound 203 has been prepared by alkylation of 0-3’ of thymidine, and was converted into the triphosphate analogue 204 by reaction with tributylammonium pyrophosphate, previously activated by carbonyldiimidazole. Initial reaction of 203 with carbonyldiimidazole led to the formation of a ‘dimeric’ pyrophosphonate of 203. Similar chemistry was also carried out on a-thymidine, and the substrate properties of the products 203 and its a-anomer towards DNA polymerases were studied.202
0
0
-
-t
202
203
Howy 204
13.4 Nucleoside Mono- and Di-phosphosugars and Their Analogues. - A synthesis of UDP-GlcNAc from UMP and GlcNAc has been developed which uses an engineered mutant.203The analogue 205 of UDP-Gal has been prepared as a potential transferase inhibitor; the synthesis involved the formation of a Chydroxymethyl compound via the reaction of tetra-0-benzyl methyl galactoside with propargyl trimethylsilane and BF3, followed by ozonolyis and reduction. Similar analogues of UDP-GlcNAc and UDP-GalNAc were also described.2M A range of analogues of CMP-NeuNAc have been reported from Schmidt’s laboratory. These include compounds in which the cytosine unit is replaced by a
276
Carbohydrate Chemistry
methoxy group or a C-linked resorcinol unit, and cases where the sialic acid moiety is modified in the N-acyl group, is replaced by a KDN unit, or modified at C-8 and C-9. All were made by reaction of sialyl phosphites with ribosyl phosphates, using phosphate-phosphate exchange. The compounds with the cytosine unit replaced were not substrates for a(2-6)-sialyltransferase, whereas the modifications at the 5,s- and 9-position of the neuraminic acid residue were t~lerated.~” The S-linked analogue of CMP-NeuNAc has been prepared; in the key step, a cytidine-5’-phosphoamidite reacted with a sialyl thiol. The product was a substrate for a-(2-3)sialyltransferase.206
-B
CH20H HoQ
w
CH20m0-CH2 OH
205
Ura
OH OH
OH OH
-0”l
206
HO OH
207
Three fluorinated sugar nucleotide analogues have been reported. L-Galactose ,and the glycosyl phoswas used to prepare GDP-6-deoxy-6-fluoro-~-~-fucose phate 206, prepared from the glycal using Selectfluor and dibenzyl phosphate, was used to make the a-anomer 207 of GDP-2-deoxy-2-fluoro-~-fucose, the pyrophosphate link being constructed chemically. A similar procedure was used to synthesize UDP-2-deoxy-2-fluoro-a-~-galactose,the fluorinated glycosyl phosphate being coupled enzymically to the UMP unit. The effects of the compounds on fucosyltransferases and sialyltransferases were studied, with which in general they acted as competitive inhibitors and formed tight complexes with the enzyrnes.*O7 In a route to biosynthetically-significant nucleotides of ketosugars, oxidation of partially-protected glycosyl H-phosphonates such as 208 (Scheme 7) with Ru04 gives ulosyl phosphates in good yield, and these can then be converted conventionally to nucleoside diphosphosugars such as 209.*08 TDP-3,6Dideoxy-P-L-arabino-hexopyranose(TDP-P-L-ascarylose) has been produced from TDP-3-deoxy-a-~-glucoseby the rhamnose-synthesizing enzyme system isolated from Salmonella entericum LTL209
~~0
O-P-OH 208
209
OH
Reagents: i, RuO2, NaI04,CH2C12/H20; ii, dTMP-rnorpholidate, MeCN; iii, LiOH aq. Scheme 7
The stereochemistry of the ADP-heptose which acts as the glycosyl donor for the heptose sugar units in bacterial lipopolysaccharides has previously been
19: Nucleosides
277
undefined, with regard to both anomeric configuration and side-chain stereochemistry. The synthesis of both anomers of ADP-L-glycero-D-mannoheptose, and of the D-glycero-isomer,has now been accomplished. Evaluation in an in vitro system in which two Kdo residues and one heptose were transferred sequentially to a synthetic lipid A analogue showed that ADP-L-glycero-P-Dmanno-heptose (210)is the natural sugar donor for the heptosyltransferases from E . coli, although the D-glycero-P-D-manno- isomer was also accepted at a considerably slower rate.210 The CDP-derivative 211 of 2-C-methyl-~-erythrito,an intermediate in the non-mevalonate pathway to isoprenoids, has been synthesized from 2-Cmethyl-~-erythritol-4-phosphateand CTP, using the transferase which produces 211 naturally.211Enzymatic routes have also been used to produce 211 with multiple specific 13C-labels,and also 2-14C-labelled The boranodiphosphate analogue 212 of ADP-glucose has been synthesized, in a procedure in which a 5‘-phosphoramidite of adenosine was treated with a borane-amine complex, and the product then deprotected and coupled with a-D-glucopyranose-1-phosphate?13 CH20H
OH 210
OH OH
211
OH OH
212
OH OH
13.5 Small Oligonucleotidesand Their Analogues.- 13.5.1 3’+5’-Linked systems; methodology and modijied internucleotidic links. New protecting groups have been developed for the internucleosidic phosphate links in oligonucleotide synthesis. The phosphoramidite 213, containing the 2-[( 1-naphthyl)carbamoyloxy] ethyl (NCE) group has been used in conventional solid-phase synthesis, and the NCE group could be removed from the assembled phosphate or phosphorothioate oligonucleotide using aqueous Other workers have studied a number of p-(heteroary1)ethyl groups, such as in 214, where a broad range of sensitivity towards base could be achieved depending on the nature of the heteroaromatic Phosphoramidites containing the 2-cyano-l-tbutylethyl protecting group have also been used for oligonucleotide synthesis.216 Phosphoramidites of 6-methyluridine and 5,6-dimethyluridine have been made and used to incorporate the bases site-selectively into oligon~cleotides.~~~ Ring-closing metathesis was applied to the phosphotriester 215 to give the conformationally restricted dinucleotide 216, as a mixture of all four diastereomers?18There has been a fuller report on the synthesis and properties of a uridylyl-(3’+5’)-thymidine dinucleotide with a link between 0-2’ of the uridine and the methyl group of the thymine base, designed to mimic the hydrogenbonded situation in certain tRNAs (Vol. 32, p. 286-287). The unit was incorporated into oligonucleotides, where a bending of the structure was demon-
278
Carbohydrate Chemistry
213
214
strated by physical rnea~urements.~~’ The same group has also prepared the cyclic phosphate 217, in which the ribose ring has a 3’-endo-geometry7and incorporated it into into oligonucleotides at the 5’-terminal site.220 This work was extended to the synthesis of the dinucleotide 218, the isomers of which, separated by chromatography, were assigned absolute configurations by CD and computational methods. Detailed conformational studies were carried out, the ‘top’ ribose unit adopting a 2’-endo-geometry and the ‘lower’one a 3’-endo-conformation. The analogous P=S species was also studied.221
w
HOCH2
Why
TbdmsOCH2
I
215
OTbdms
OH 216
I
OH OMe 217
OMe
OH OMe 218
In continuation of work in Just’s laboratory on the diastereoselective synthesis of dinucleoside phosphorothioates, the chlorophosphoramidite 219 (for the synthesis of the aminoalcohol see Chapter 14) was converted as indicated in Scheme 8 into the &-isomer 220, in a 6:l ratio with the diastereomer, and this ratio could be improved by the use of a more hindered base in step ii.222The auxiliary 221, derived from L-tryptophan, has also been used. When 221 was treated sequentially with 5’-O-Tbdms-thymidine, 3’-O-Tbdms-thymidine and Beaucage’s reagent, a phosphorothioate triester was produced. The auxiliary could be removed as the aminomethyl compound by treatment with ammonia, to give the Rp-isomer of 220, in 40:l excess.223 The influence of diastereomeric ratios of deoxyribonucleoside phosphoramidites on the synthesis of phosphorothioate oligonucleotides has been investigated. Almost diastereomerically-pure phosphoramidites were found to give an almost equal mixture of diastereomers of a monophosphorothioate d e ~ a m e rA. facile ~ ~ ~ synthetic route to dimeric phosphorothioate building blocks 222 has been developed. Dinucleoside phosphite triesters were obtained in a one-pot procedure by sequential coupling to PC13of protected nucleosides with
279
19: Nucleosides
MeY Me 0 PiNH
i, ii
bH2CN Me &H2CN Me 220 OH 219 Reagents: i, 5’-OTbdms-thymidine, Et3N; ii, 3’-OTbdms-thymidine, 2-bromo-4,5-dicyanoimidazole; iii, Beaucage’s reagent; iv, NH3 aq., then TBAF Scheme 8
0
free 5’- and 3’-hydroxy groups, followed by cyanoethanol. Subsequent sulfurization gave the products 222.225Diastereomeric S-methyl compounds 223 have been made by reaction of the dinucleoside phosphorothioates with Me1 and pyridine.226
w
DmtrOCH2
(-i0 I
0 -C @
CN
222
OLev
0
HO’
OLev 223
‘
w
O-CH2
OH OHra
224
There has been a fuller account of the preparation of 3’-thiouridine dinucleotide 224 (Vol. 30, p. 280-281), and a detailed study was made of its stability in acid and base. It was less stable in acid than the parent dinucleotide, and the initial product of treatment either with acid or at pH 10 was 3’-thiouridine 2’,3’-cyclic pho~phorothioate.2~~ A previously-reported bicyclic 3’-aminonucleoside has now been converted to the dinucleotide building block 225, which caused a reduction in T, values when incorporated into oligonucleotides.228 There has been an extended and expanded account of the preparation of dideoxynucleoside boranophosphates through the intermediacy of H-phosphonate diesters. The conversion of these to the boranophosphates proceeds with retention of onf figuration?^^ Workers at Isis Pharmaceuticals have developed methods for the synthesis of chimeric oligonucleotides containing blocks of phosphodiester, phosphorothioate and phosphoramidate internucleosidic links. H-Phosphonate
280
Carbohydrate Chemistry
methodology was used, and methods were developed for conversion of a block of H-phosphonate diester links into the required final internucleosidic links without affecting those of other types already in place. The installation of PO groups in the presence of PS and PN units required oxidation with trithylamine in CC&/pyridine/water.ZU)
wy ODmtr
I
0-P=O
I
225 OeCN
I
OTbdps 226
An improved procedure has been developed for the preparation of vinylphosphonate-linked dinucleotide analogues such as 226. The method involves the coupling of an H-phosphonate diester at 0 - 3 ’ of the ‘top’ nucleoside with a @-bromovinylderivative of thymidine, using palladium catalysis. Optimization studies were carried out, and under the best conditions, yields were high.231 The L-enantiomers of deoxycytidine and deoxyguanosine have been incorporated into the middle of a decadeoxynucleotide, and the effects on the conformation were A number of references to the incorporation of modified nucleosides into oligonucleotides are given elsewhere in this chapter, and some relevant chemistry of protecting groups in discussed in Section 15. A reference to altritol nucleic acids is mentioned in Section 16. 13.5.2 5‘+5’-Linked systems. Treatment of inosine 5’-methylenephosphonate with Im3P0 gave the [bis(inosine-S)]-tetraphosphate analogue 227, with two methylene replacements, together with the [bis(inosine-5’)l-pentaphosphate analogue.233 An improved route has been developed for the synthesis of the carbocyclic analogue 228 of cyclic IDP-ribose (see Vol. 32, p. 289). In the new approach, the intramolecular formation of the pyrophosphate link was carried out efficiently using an S-phenyl phosphorothiate at 0-5‘ of the ribose unit, activated by iodine, and there was no need to install a bromine atom at C-8 of the hypoxanthine in order to bias the conformation in favour of cycli~ation.2~~ This strategy of conformational restriction was used in chemistry en route to cyclic ADP-carbocyclic ribose, in which the pyrophosphoryl macrocycle was formed, but final deprotection was not rep0rted.2~~ Some chemistry directed towards the synthesis of cyclic IDP-glucose has been described, but the pyrophosphate link was not e~tablished.2~~
28 1
19: Nucleosides
OH OH
228
14
OH
OH
Oligonucleotide Analogues with Phosphorus-free Linkages
In the area of amide replacements, Robins’s group have reported the synthesis of the active ester 229 and its reaction with the amine 230 (Scheme 9) to give the trinucleotide analogue 231,capable of further extension using 229 after reduction of the azide to an amine. This iterative procedure was used to produce a pentanucleotide analogue, and alternatively coupling of two dimeric units was used to make a tetramer with a 3’-terminal hydroxy group.237Other workers have reported the synthesis of C-T dinucleotide analogue with the same amide replacement and its incorporation at the cleavage position of a hammerhead ribozyme substrate. The analogue had high affinity for the ribozyme but did not undergo hydr0lysis.2~~ A similar U-G dinucleotide analogue has also been made, the amide bond being introduced by reaction of a 5’-amino-5’-deoxyguanosine with a 2’,3’-butyrolactone on the uridine unit. This unit was incorporated into a hammerhead ribozyme to give a catalytically active species which was stable to RNase A degradation.239
wra
“-Bra
OyCH2
H2N-CH2
w
Ns-CH2
O y C H 2 0 T b dam s 0
--QNO2
229 Reagents: i, diglyme, 65 OC
O y C H 2 OTbdms HN,
+ 0
Rra CH2OTbdms
YOEt
230
Scheme 9
OTbdms
HN ,
C H 2,0 HN.
w
OTbdms
a
OEt
231
282
Carbohydrate Chemistry
The thymidine dimers 232 (R = Me, Bn), with 0-alkylhydroxamate links, have been prepared.240When the 0-methyl compound was incorporated into oligonucleotides, only minor changes in T, values were observed for duplexes with either complementary RNA or DNA, but significant decreases were found using the 0-benzyl species. The very similar N-benzyloxycarbamate 233 has also been synthesized, and up to three replacement linkages were incorporated into a thymidine 16-mer, from which the benzyl groups could be removed by hydrogenolysis. The oligomers with N-benzyloxy groups showed significant decreases in T, values for duplexes with poly-dA, but the decrease in stability was less for the N-hydroxy-species.The presence of the N-hydroxycarbamate links increased stability of the oligonucleotides towards nuclease S1, and the oligomers formed Fe(II1) complexes.241The bicyclic aminonucleoside which was used in the formation of 225 has also been combined with a thymidine unit to give a carbamatelinked dinucleotide analogue, incorporation of which into oligonucleotides caused significant decreases in duplex stability.228
uy vy DmtrOCH2
DmtrOCH2
OH
232
OH
233
Fmoc 234
Workers at Novartis have prepared structures 234 (B = Thy, Cyt, Ade) from D-hydroxyproline, and have assembled them into amide-linked oligonucleotide analogues by conventional solid-state peptide synthesis. A homopyrimidine oligomer bound to complementary RNA with significant affinity, whilst no binding was observed with complementary DNA.242 A new approach to 3’-deoxy-3’-C-formylribonucleosides involves (Scheme 10) the synthesis of 235 from D-xylose; stereoselective reduction with LiAlH4to give the saturated dithiane was followed by attachment of the base and liberation of the aldehyde 236. This was converted as indicated into the methylene(methy1imino)-linked dimer 237, with 2’-hydroxy and methoxy groups. This was used to make oligonucleotides with alternating phosphodiester and methylene(methy1imino) links, which showed good increases in T, against RNA complements.243 The formacetal-linked dimer 238 was prepared, using the 3‘-methylthiomethyl ether as an intermediate, and activating it for coupling using NBS. Photolysis of 238 gave the analogue 239 of a DNA photodecomposition product. This analogue was incorporated into oligonucleotides for comparison with the phosphate-linked
283
19: Nucleosides
FH20H
I
-
C O ,
+ OHC OH 236 Reagents: i, PPTS, then BH3.py
TbdpsO
AThY
TbdpsOqq$Me
Scheme 10
OTbdms 238
15
OMe
n
OTbdms 239
Ethers, Esters and Acetals of Nucleosides
15.1 Ethers. - A large-scale synthesis of 2’-O-methyluridine has been reported, involving the formation of the 2,2’-anhydronucleoside and its subsequent ringopening with magnesium methoxide. The method could also be applied to the synthesis of other 2’-O-alkyluridine~.~~~ Several improved procedures have been described for making 2’-O-methyl-adenosine and -guanosine, and some N-acyl derivatives. These include the preparation of 2’-O-methyladenosine by transglycosylation of a 2’-O-methylcytidine derivative, itself accessible via an anhydronucleoside, and the selective 2’-O-methylation of 2-amino-6-chloropurine riboriboside side followed by base modification. Also, 3’,5’-Tipds-2,6-diaminopurine can be methylated at 0-2’, followed by modification of the base, and selective 2’-O-methylation of l-benzylinosine could be accomplished using trimethylsulfonium Reaction of N-benzyloxymethyl-5-methyluridinewith cyclic sulfates gave the 2’-O-alkylated compounds 240 (n= 2,3), in a ca. 3:l ratio with the 3’-regioisomer. The sulfate could then be displaced with dimethylamine to give after further manipulation the intermediates 241 (n = 2, 3), and similar (methy1thio)alkyl ethers could be made using methanethi01.~~~ The 3-(dimethy1amino)propylcompound 241 (n = 3) has been incorporated into oligonucleotides, which showed very high nuclease resistance, as did the previously prepared 3-aminopropyl systems, and maintained high binding affinity to target RNA when a few of the
284
Carbohydrate Chemistry
modifications were dispersed throughout the oligon~cleotide?~~ The same team, from Isis Pharmaceuticals, have also made the related species 242 (R = Me, Et) via the intermediacy of a 2’-O-(2-hydroxyethyl)-nucleosideand the N-alkoxyphthalimide derived from it by Mitsunobu reaction. Again, these modifications, when introduced into oligonucleotides, gave high binding affinity to complementary RNA (but not DNA) and good nuclease stability.249 Other workers have prepared 2’-0-methoxycarbonylmethyl- and 2’-0-(2,3-dibenzoyloxypropyl)-derivatives of nucleosides by alkylation of 3’,5’-Tipds derivatives, and these were used to make oligonucleotides with carboxymethyl, 2,3-dihydroxypropyl and 2-oxoethyl ethers at O-2’.250
uy Hh
DmtrOCH2
HOCHZ
DmtrOCH2
OH ‘0
osog240
(C\Hdn NMe2 241
OH OI 0 I
242 NR2
The bisubstrate inhibitors 243 of catechol-0-methyltransferase have been prepared by base-sugar coupling, after attachment of the aminoethyl spacer to a ribose derivative. The adenosine analogue was ten times more effective than the compound in which the nucleoside unit was replaced by a methyl In somewhat similar fashion, 0-3’ of the aminoglycoside antibiotic neamine has been linked to 0-5’ of adenosine by chains of between five and eight methylene units, in order to make bisubstrate inhibitors for aminoglycoside 3’-phosphotransferase, an enzyme which phosphorylates the antibiotic using ATP and thus conveys bacterial resistance. The six- and seven-carbon tethers proved most The 3-bromopropyl-substituted nucleoside phosphoramidite 244 has been prepared, with a view to its incorporation into oligonucleotides which would permit post-synthetic functionalization of the sugar moiety on the solid support by reaction with appropriate n u ~ l e o p h i l e s . ~ ~ ~ Ceric ammonium nitrate on silica gel has been used for the rapid cleavage of trityl, Mmtr and Dmtr ethers from primary alcohol groups of nucleoside and nucleotide derivatives. Primary Tbdms and Tips ethers were also cleaved, the silica gel adding considerably to the catalytic The selective hydrolysis of a Tbdms protecting group at 0-5’ of multisilylated nucleosides has been carried out in high yields using a mixture of TFA, water and THF in the proportions 1:1:4, at 0 0C.255The same method also liberates the 5’-hydroxyl group selectively when it is applied to 3’,5’-Tipds-protectednucleosides, with 245 being produced in 95% yield.256 15.2 Esters. - A Pseudomonas lipase deposited on ceramic particles or on diatomite can acetylate 2’-deoxynucleosides regioselectively at 0-3’ by acetyl
285
19: Nucleosides
I
O-CN
244
245
transfer from various O-acetyl-aldoximes or - k e t o x i m e ~Amano . ~ ~ ~ A lipase will selectively remove the three O-acetyl groups from 4-N-acetyl-2’,3’,5’-tri-Oacetylcytidine, whereas Burkholderia cepacia esterase will remove selectively the 5’-O-acetyl group from the same The ester 246 has been prepared as a potential bioreductively-activated prodrug of 5-fluoro-2’-deoxyuridine(FUDR). It was resistant to human serum esterases due to the steric hindrance of the a-methyl groups, but chemical reduction led to rapid release of FUDR by intramolecular aminoly~is.~’~ When the ester 247 was treated with lauroyl peroxide in the presence of 15 equivalents of styrene, the polymer 248 was obtained. This was soluble in many common organic solvents but which could be precipitated with methanol, making the technique potentially useful for parallel synthesis.2605‘-O-Methacryloyluridine and -adenosine have been polymerized onto a silica support, using Cu(1) mediated radical polymerization, under conditions favouring products of narrow polydispersity.261 CH20H
0
OH
246
247
OEt 248
249
OH OH
Analogues 249 (X = H, OH) of UDP-GlcNAc have been prepared as potential inhibitors of chitin synthetases. The synthetic route involved a C-ally1 derivative of GlcNAc, which was elaborated by ozonolysis, Wittig reaction and coupling with the nucleoside, followed by hydrogenation or hydroxylation as appropriate. The corresponding amides were also prepared from 5’-amin0-5’-deoxyuridine.~~~ Lipophilic amino acid methyl esters and methylamides have been coupled to 0-5’ of AZT by carbamate links. The products showed anti-HIV activity, but this was not due to carbamate hydrolysis or to direct inhibition of reverse transcriptase, and the mechanism of action may be one not previously observed with nucleoside a n t i v i r a l ~ . ~ ~ ~ Adenosine has been converted regioselectively to its 2‘-tosylate in 90% yield by treatment with TsCl and Et3N in acetonitrile, in the presence of substoichiometric amounts of organotin reagents such as Bu2SnC12or B U ~ S ~ O . ~ ~
286
Carbohydrate Chemistry
15.3 Acetals. - In continuation of work on protecting groups suitable for use at 0-2’ during oligoribonucleotide synthesis, Reese and co-workers have studied the properties of a range of l-aryl-4-alkoxypiperidin-4-yl groups, leading to the development of the 1-(4-chlorophenyl)-4-ethoxypiperidin-4-yl (Cpep) group (as in 250). This group has greater stability at pH 0.5 and greater lability at pH 3.75 than a number of alternatives such as the previously-used Ctmp and Fpmp
The 2’-O-(3-bromopropoxy)methyl group has been introduced at 0-2’ of ribonucleosides, permitting post-synthetic functionalization of the sugar units of oligonucleotides on the solid support by nucleophilic Ribonucleoside 2’- and 4’-O-methylthiomethyl derivatives have been synthesized directly from selectively protected nucleosides by reaction with DMSO-Ac20-AcOH mix t ures?66 To study the structural requirements of the binding of aminoglycosides to nucleic acids, the conjugate 251, related to the naturally-occurring nucleoside J, has been prepared and incorporated into oligonucleotides. This led to stabilization of duplexes, which was most marked with complementary RNA.267
I-0- CI
250
16
OH 251
Other Types of Nucleoside Analogue
A review has been given of the synthesis and biological activity of isonucleosides, analogues in which the heterocyclic base occupies a non-anomeric position.268 There have been reports on the synthesis of isonucleosides of type 252, with R = ~269,270 or CH20H.270 Isonucleosides related to bioactive benzimidazole nucleosides have been prepared, including 253, made by displacement of a tosylate with 2-bromo-5,6-dichlorobenzimidazoleunder phase-transfer conditions, followed by reaction with isopropylamine. The 3’- and 5‘-deoxy-analogues of 253 were also reported.271Chain-extended compounds 254 have been synthesized from D-glucose, the base (Ade, Ura, 5-fluoro-Ura, Thy) being introduced by reaction with an epoxide at a late The species 255 (B = Ade, Ura, 5-fluoro-Ura, Thy) have also been prepared; again the base was introduced by reaction with an epoxide, itself prepared from D-glucosamine through the intermediacy of 2,5anhydro-~-rnannitol?~~ Compounds enantiomeric with 255 have been reported previously from the same laboratory (Vol. 31, p. 128). Isonucleosides 256 (B = e.g. Ade, g-aza-Ade, Cyt) with an exocyclic methylene group have been prepared, using a keto-sugar derived from D-xylose as an intermediate, and introducing the nucleobases using Mitsunobu reactions. The compounds did not have significant anti-HIV The iso-C-nucleosides 257 (R = Ph, Me) have been
287
19: Nucleosides
A
252
253
OH
254
OH
255
257
synthesized, again using D-xylose as precursor, and the 3'-epimers were also produced.275 There has been a further report on altritol nucleic acids (ANA, 258) (see Vol. 33, p. 316), which notes that they are superior to the corresponding DNA, RNA or hexitol nucleic acids (as 258, but lacking the hydroxy groups) in supporting efficient non-enzymatic template-directed synthesis of complementary RNAs from nucleoside 5'-phosphoro-2-methylimidazolides~76
*
0 OH
258
Further reports have appeared concerning dioxolane and oxathiolane nucleoside analogues. Compounds of these types, in both enantiomeric series, have been reported with 5-(2-halovinyl)uracils as bases, and the dioxolanes in the L-series showed potent anti-VZV activity.22Dioxolane analogues with 5-azacytosine and 6-azathymine as base have been prepared in both enantiomeric series, and as a- and P-anomers. The compound 259 of the L-series showed significant activity against HBV, whilst the enantiomer of 259 has potent antiHIV Similar oxathiolanes in the L-series, with 6-azacytosine, 5-azacytosine, and various 3-deazapyrimidines as base, have been prepared by chemical transglycosylation of 3-TC.278Racemic oxaselenolanes 260 have been made, along with the a-anomers. The enantiomers of 260 were separated by chiral HPLC. Anti-HIV and anti-HBV activity was found for the cytidine and 5fluorocytidine analogues, and this was greatest for the (-)-isomers, as in the case for 3-TC, but activities were significantly less than for 3-TC.279New prodrugs for 3-TC have been reported, in which polyaminated sidearms are attached at either 0-5' or N-4, or both positions, with a view to using the polyamine transport system for incorporation of the drug. Some compounds reported had good antiviral activity.280The dioxolane and oxathiolane derivatives 261 (X = 0,S; R = H, Me) have been prepared, along with the trans-isomers, but did not show significant antiviral activityF8'
288
Carbohydrate Chemistry
J? $J
O
N p j H 2 0 H
qy
k..
pj
CH20H
CH20H
se
259
260
261
The isoxazolidine 262 was the major isomer formed by cycloaddition of vinyl acetate with a nitrone derived from isopropylidene-D-glyceraldehyde.Further chemistry then led to the L-nucleoside analogue 263. Reaction of the same nitrone with 1-vinylthymine also gave diastereoselectively a cis-disubstituted isoxazolidine which could be converted to the same enantiomer 263.282An alternative route to 263 and its uracil analogue involves the BF3-catalysed reaction of the nitrone with the Tbdms ketene acetal of methyl acetate, which proceeds with the same facial selectivity as the cy~loadditions.~~~ In a comprehensive paper, the use of serine-derived starting materials has led to the synthesis of isoxazolidinyl analogues of the polyoxins. Thus, for example, the isoxazolidinone 264 was prepared stereoselectively through Michael addition of N-benzylhydroxylamine to an enoate derived from D-serine, and could be converted to the nucleoside analogues 265. Additions of silyl ketene acetals to nitrones, and cycloadditions of nitrones with vinyl acetate, were also used to make oxazolidines, and appropriate choice of protecting groups and chirality of serine permitted access to all possible stereo~hemistries.2~~
Bn’
262
263
Bn
Bn’
264
- 1
tm
265
A series of papers from Vasella’s laboratory has discussed the synthesis of oligonucleotide analogues that possess a ‘nucleobase-including’ backbone, with the 3’,5’-phosphodiester link replaced by an acetylenic link between C-5’ of the ribose and C-6 of uridine or C-8 of adenosine. The bis-uridine 266 was made using Sonogashira coupling of a C-5‘-alkyne with a 6-iodo~ridine.~” The 8iodoadenosine derivative 267 was prepared by addition of Tms-acetylide to a C-5’ aldehyde?86Other workers have reported a stereocontrolled route to a similar non-iodinated adenosine derivative through diastereoselective reduction of a ribofuranosyl acetylenic ketone, followed by introduction of the adenine A bis-adenine unit was made by Sonogashira coupling,288and an adenosine tetramer 268 was obtained by coupling an iodinated dimer with an eth ynylated dimer.289 3’-O-Thiocarbamoylthymidinehas been converted into various species with heterocycles joined to thymidine through an ether link.290Water-soluble Clinked nucleoside-porphyrins have been made by reaction of 2’,3‘-0-isopropylideneuridine-5’-carboxaldehydewith pyrrole to give a dipyrromethane, which was treated with p-fluorobenzaldehyde to give after oxidation a porphyrin
289
19: Nucleosides
with uridine units at opposite meso-positions, into which Pd(I1) could be inserted. The Pd(I1) metalloporphyrin was an efficient reagent for selective cleavage of double-stranded DNA in visible light.291 NHBz
0 0 MeX Me
OX0 Me Me 266
268
267
Nucleoside analogues 269 (B = Ade, Gua, Thy) have been made as ra~ e m a t e s . 2The ~ ~ antiviral activity of synadenol has led to the synthesis of the related cyclopropanes 270 and its E-isomer, which did not have useful antiviral activity.293 The cyclobutane 271, and its E-isomer, and the cyclohexenes 272 and 273 have also been described.294 Various pyrimidine nucleosides of type 274 have been made (for related purines, see Vol. 32, p. 297), and the BVDU analogue shown had the best anti-VZV activity.29sThe cyclopropanes 275, involving all five main nucleobases, have been made in chiral form, the Ade and Gua compounds having moderate anti-HIV The bicyclo[2.l.l jhexane nucleoside analogues 276 have been and cyclopentane nucleoside analogues such as 277 have been made from the iridoids geniposide and a ~ c u b i n . 2 ~ ~
0
I
LcH2
HOH2C
17
V
HOH2C
CH20H
274
6
CH2Ade
B ' v y r N O
275
.Ade/Cyt
276
HOH2C
HOH2d 277
Reactions
The reactions of some 5'-protected pyrimidine ribonucleosides with phosphoryl chloride and pyridine in dichloromethane, followed by reaction with excess of an alcohol, have been studied. It was claimed that the first step of this procedure led to a mixture of the 2'- and 3'-phosphorodichloridates (e.g. 278 and its regioisomer). Since the rate of the subsequent alcoholysis to give a mixture of the 2'and 3'-phosphotriesters was considerably faster that the corresponding cases using 2'-deoxynucleosides, it was thought that the adjacent cis vicinal hydroxyl group was involved in hydrogen bonding to the P=O unit, thereby accelerating
290
Carbohydrate Chemistry
the displacements of chloride by electrophilic catalysis.299Other workers, however, have reinterpreted the NMR data on which this theory was based, and have concluded that the intermediates in this reaction sequence are the two diastereomers of the cyclic phosphorochloridates such as 279.3M) The hydrolysis of the the 3’-thioinosine derivative 280 has been studied over a 0
Qy
TrOCH2
0
‘pl’p
CI’ \CI 278
279
280
wide acidity range. At pH >3, only hydroxide ion catalysed isomerization to the 2-phosphotriester is observed, whereas under more acidic conditions hydrolysis to the 2’-monomethylphosphate and 3’-S-monomethylphosphorothiolate competed. The latter was the only product to accumulate in very acidic solutions, and mechanisms were discussed?01Uridylyl-(3’,5’)-8-carbomethoxyaminoadenosine has been synthesized, and its transesterification to uridine 2‘,3’-cyclic phosphate has been studied in the presence and absence of Zn2+ions. The carboxylate in the vicinity of the phosphodiester bond accelerated the cleavage in the presence of Zn(I1) ions, but not when the metal was not present.302 In connection with mechanisms for the alkaline hydrolysis of DNA, the kinetics of hydrolysis of thymidine 3’-phosphodiesters with alcohols such as 2,2,2-trichloroethanol, and also of thymidinyl-(3’-5‘)-thymidine,have been studied. With the trifluoroethyl phosphate, the 3’,5’-cyclic phosphate is an intermediate in alkaline hydrolysis, but this was not the case with the dinucleotide. Studies using density functional theory calculations were also reported.303 The hydrolysis of the cyclic phosphorothiolate 281 has been studied between pH -2 and pH 7.6. Below pH 2, the products 282 and 283 were obtained with 283 predominating, whereas between pH 2 and pH 5, the cyclic phosphorothiolate 282 was the main product. Above pH 5, 283 and 284 were obtained, with the latter predominating by 2:l. Mechanisms were discussed, with the uncatalysed reaction to give 282 occurring through attack of water on the methyl group, with C-0 bond cleavage.304
MeO,
;’
?
pThy I pThy O-CH2
O-CH2
---+
HO,
+
/p\
281
0
282
s
Me0 OH 283
SH 284
Radicals generated by reaction of cytidine with the sulfate radical-anion in aqueous solution have been characterized by EPR spectroscopy. Radicals were
19: Nucleosides
29 1
generated either in situ in a continuous-flow system, or the sulfate anion radical was generated in the presence of 2-methyl-2-nitrosopropane. In the continuousflow system, the sugar radical 285 was observed, but the intensity of this decreased in the presence of phosphate dianion, with a base radical of indeterminate structure being formed. In the spin-trapping experiments the persistent radical 286 was detected in the absence of phosphate, but with phosphate dianions present, spin-trapped radicals on the base were observed. The results were interpreted in terms of competition between reaction of the intermediate base radical-cation with phosphate dianion and radical transfer to the sugar.305 The radical 287 was made by photolysis of a benzylcarbonyl precursor. Its radical recombination and hydrogen abstracting characteristics suggested that it could abstract a hydrogen atom from deoxyribose and thus transfer radical character to the sugar of a neighbouring nucleotide in DNA.306A model compound has been used to study the effects of thiiyl radicals on nucleosides, of relevance to radical damage to DNA. The work supported the proposal that thiiyl radicals can add at C-6 to pyrimidine n u c l e o ~ i d e sAn . ~ ~investigation ~ has been made of the mechanism of direct strand cleavage induced by anaerobic irradiation of DNA containing 5-bromouracil. An oligonucleotide fragment containing 2-(adenin-9-yl)furanat the 3’-terminus was found as a major photoproduct .308
CH20H N
OH 285
286
OH
287
OH
HO’ ‘0’ 288
Photolysis of 1-(2’-deoxyribosyl)-7-nitroindolewas presumed to give the diradical 288, and hence, by radical recombination and fragmentation, the observed photoproducts 2-deoxyribonolactone and 7-nitrosoindole. When the 7-nitroindole nucleoside was incorporated into oligodeoxynucleotides, protolysis led to the formation of abasic positions.309 When oligonucleotide chains incorporating the 4’-C-pivaloylthymidine unit 289 are irradiated in the absence of radical traps, the cation-radical 290 (Scheme 11) is produced, which is capable of undergoing reduction by electron transfer from a nearby guanosine unit to give 291, which on enzymic digestion gives the 3’-ene 292. Variation of the nucleotide sequence demonstrated a strong distance dependence of the electron transfer rate, which was more efficient with 8oxoguanosine as electron donor. The enol ether 292 was independently synthesized using reductive elimination from a 4’-phenylselenyl thymidine derivative to install the double bond.310 The degradation of hexopyranosyl cytosine nucleosides in buffers of acid, neutral and alkaline pH has been followed by HPLC. The compounds were found to degrade by hydrolysis to cytosine and/or deamination to the corresponding uracil nucleoside~.~’
292
Carbohydrate Chemistry
-
T
I
0
0
I
289
1
aThy4 aTh
HO-P=O 1 0\CH2 290
Scheme 11
291
"OhH2
292
References 1. 2.
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263. S. Chang, G. Griesgraber, T.W. Abraham, T. Garg, H. Song, C.L. Zimmerman and C.R. Wagner, Nucleosides, Nucleotides, Nucleic Acids, 2000,19,87. 264. M. Kawana, M. Tsujimoto and S . Takahashi, J . Carbohydr. Chem., 2000,19,67. 265. W. Lloyd, C.B. Reese, Q. Song, A.M. Vandersteen, C. Viscontin and P.-Z. Zhang, J . Chem. SOC.,Perkin Trans. I , 2000,165. 266. A.E. Pechenov, S.G. Zavgorodny, V.I. Shvets and A.I. Miroshnikov, Russ. J . Bioorg. Chem., 2000,26,327 (Chem. Abstr., 2000,133,177 398). 267. R. Tona, R. Bertolini and J. Hunziker, Org. Lett., 2000,2, 1693. 268. K. Walczak, Pol. J . Chem., 1999,73,1613 (Chem. Abstr., 2000,132,12 448). 269. H. Zhang, M. Zhang, Z. Piao, L. Ma and L. Zhang, Yaoxue Xuebao, 1999,34,363 (Chem. Abstr., 2000,132,64474). 270. B.-H. Yang and X.-J. Wu, Chin. J . Chem., 2000,18,118 (Chem.Abstr., 2000,132,222 789). 271. G.A. Freeman, D.W. Selleseth, J.L. Rideout and R.J. Harvey, Nucleosides, Nucleotides, Nucleic Acids, 2000,19, 155. 272. X.B. Tian, J.M. Min and L.H. Zhang, Tetrahedron: Asymmetry, 2000,11, 1877. 273. Z. Lei, J.M. Min and L.H. Zhang, Tetrahedron: Asymmetry, 2000, 11, 2899. 274. S. Bera and V. Nair, Helv. Chim. Acta, 2000,83, 1398. 275. W.D. Wu, L.T. Ma, L.H. Zhang, Y. Lu, F. Guo and Q.T. Zheng, Tetrahedron: Asymmetry, 2000,ll, 1527. 276. I.A. Koslov, M. Zielinski, B. Allart, L. Kerremans, A. Van Aerschot, B. Busson, P. Herdewijn and L.E. Orgel, Chem. Eur. J., 2000,6,151. 277. M.-Z. Luo, M.-C. Liu, D.E. Mozdziesz, T.-S. Lin, G.E. Dutschmann, E.A. Gullen, Y.-C. Cheng and A.C. Sartorelli, Bioorg. Med. Chem. Lett., 2000, 10, 2145. 278. M.-C. Liu, M.-Z. Luo, D.E. Mozdziesz, T.-S. Lin, G.E. Dutschman, E.A. Gullen, Y.-C. Cheng and A.C. Sartorelli, Nucleosides, Nucleotides, Nucleic Acids, 2000,19, 603. 279. C.K. Chu, L. Ma, S. Olgen, C. Poerra, J. Du, G. Gumina, E. Gullen, Y.-C. Cheng and R.F. Schinazi, J . Med. Chem., 2000,43,3906. 280. N. Mourier, M. Camplo, G. S. Della Bruna, F. Pellacini, D. Ungheri, J.-C. Chermann and J.-L. Kraus, Nucleosides, Nucleotides, Nucleic Acids, 2000, 19, 1057. 281. N. Nguyen-BayN. Lee, L. Chan and B. Zacharie, Chem. Commun., 2000,2311. 282. P. Merino, E.M. del Alamo, S. Franco, F.L. Merchan, A. Simon and T. Tejero, Tetrahedron: Asymmetry, 2000,56,2995. 283. P. Merino, E.M. del Alamo, M. Bona, S. Franco, F.L. Merchan, T. Tejero and 0. Vieceli, Tetrahedron Lett., 2000,41,9239. 284. P. Merino, S. Franco, F.L. Merchan and T. Tejero, J . Org. Chem., 2000,65,5575. 285. S . Eppacher, N. SolladiC, B. Bernet and A. Vasella, Helu. Chim. Acta, 2000, 83, 1311. 286. H. Gunji and A. Vasella, Helv. Chim. Acta, 2000,83, 13 11. 287. T. Umino, N. Minakawa and A. Matsuda, Tetrahedron Lett., 2000,41,6419. 288. H. Gunji and A. Vasella, Helv. Chim. Acta, 2000,83,2975. 289. H. Gunji and A. Vasella, Helu. Chim. Acta, 2000,83,3229. 290. G. Prestat, D. Dubreuil, A. Adjou, J.P. Pradhe, J. Lebreton, M. Evers and Y. Henin, Nucleosides, Nucleotides, Nucleic Acids, 2000,19,735. 291. M. Cornia, M. Menozzi, E. Ragg, S. Mazzini, A. Scarafoni, F. Zanardi and G. Casiraghi, Tetrahedron, 2000,56,3977. 292. C. Lescop and F. Huet, Tetrahedron, 2000,56,2995. 293. Y.-L. Qiu, M.B. Ksebati and J. Zemlicka, Nucleosides, Nucleotides, Nucleic Acids, 2000,19,31.
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Carbohydrate Chemistry
294. H.-P. Guan, M.B. Ksebati, E.R. Kern and J. Zemlicka, J . Org. Chem., 2000, 65, 5177. 295. T. Onishi, C. Mukai, R. Nakagawa, T. Sekiyama, M. Aoki, K. Suzuki, H. Nakazawa, N. Ono, Y. Ohmura, S. Iwayama, M. Okunishi and T. Tjuji, J. Med. Chem., 2000,43,278. 296. C. Pierra, S. Olgen, S.C.H. Cavalcanti, Y.-C. Cheng, R.F. Schinazi and C.K. Chu, Nucleosides, Nucleotides, Nucleic Acids, 2000, 19,253. 297. G. Wang, Tetrahedron Lett., 2000,41,7139. 298. H. Franzyk and F.R. Stermitz,J . Nat. Prod., 1999,62,1646(Chem.Abstr., 2000,132, 122 846). 299. C.D. Roussev, G.D. Ivanova, E.K. Bratovanova and D.D. Petrov, Angew. Chem. Int. Ed. Engl., 2000,39,779. 300. P.M. Cullis, M.J.P. Harger and M. Lee, Angew. Chem. Int. Ed. Engl., 2000,39,4245. 301. M.I. Elzagheid, E. Maki, U. Kaukinen, M. Oivanen and H. Lonnberg, Nucleosides, Nucleotides, Nucleic Acids, 2000,19,827. 302. S. Mikkola, M. Oivanen, K. Neuvonen, S. Piitari, K. Kekomaki and H. Lonnberg, Nucleosides, Nucleotides, Nucleic Acids, 2000,19, 1675. 303. N. Takeda, M. Shibata, N. Tajima, K. Hirao and M. Komiyama, J. Org. Chem., 2000,65,4391. 304. M.I. Elzaghheid, K. Mattila, M. Oivanen, B.C.N.M. Jones, R. Cosstick and H. Lonnberg, Eur. J. Org. Chem., 2000,1987. 305. H. Niehaus and K. Hildenbrand, J. Chem. SOC.,Perkin Trans. 2,2000,947. 306. A.A. Anderson, J.-T. Hwang and M.M. Greenberg, J. Org. Chem., 2000,65,4648. 307. K.N. Carter, T. Taverner, C.H. Schiesser and M.M. Greenberg, J. Org. Chem., 2000, 65,8375. 308. K. Fujimoto, Y. Ikeda and I. Saito, Tetrahedron Lett., 2000,41,6455. 309. M. Kotera, Y. Roupioz, E. Defrancq,A.-G. Bourdat, J. Garcia, C. Coulombeau and J. Lhomme, Chem. Eur. J., 2000,6,4163. 3 10. E. Meggers, A. Dussy, T. Schafer and B. Giese, Chem. Eur. J., 2000,6,485. 311. G.N. Thoithi, A. Van Schepdael, R. Busson, G. Janssen, A. Van Aerschot, P. Herdewijn, E. Roets and J. Hoogmartens, Nucleosides, Nucleotides, Nucleic Acids, 2000,19,189.
20
Enzymes in Mono- and Oligo-saccharide Chemistry
1
General
Chapters 3 and 4 contain many references to the use of enzymes in the synthesis of glycosides, and di- and higher saccharides. Specific reviews have described both the traditional method of enzymatic glycosylation and some novel approaches which were designed to improve the efficiency of reactions involving poorly water soluble alcohols,' and the enzymatic synthesis of oligosaccharides on a preparative scale (greater than milligram quantities).* Several general reviews on recent developments in enzymeThose that directly relate catalysed syntheses of carbohydrates have to specific subjects are detailed in the appropriate following sections.
2
Enzymes in Synthesis
2.1 Aldolases and Ketolases. - Kajimoto has reviewed aldolase-catalysed synthesis of various azasugars (45 refs.) using fructose-1,6-diphosphate-aldolaseand other dihydroxyacetone phosphate (DHAP)-dependent aldolases in the key step.6A recent review of enzymatic preparations of monosacccharides, oligosaccharides and related compounds based on aldolases has been published.' Protecting group-free chemoenzymatic syntheses of the tetrahydroxylated pyrrolizidines australine (1) and 7-epialexine (2) have been achieved by fructose 1,6-diphosphate aldolase-catalysed reaction of dihydroxyacetone phosphate with appropriate aldehydes" Similar procedures involving coupling of DHAP with co-phosphonylated a-hydroxyaldehydes have been used to prepare a set of unnatural wphosphonic sugars 3 (Scheme l).9 Short syntheses of L-fucose analogues have been achieved (3 enzymatic steps) by aldol condensation of DHAP with various a-hydroxyaldehyde derivatives (using L-fuculose phosphate aldolase), followed by phosphate hydrolysis (alkaline phosphatase) and subsequent ketol isomerization (L-fucose isomerase).lo Selective I3C-labellingof thymidine in all positions of the 2'-deoxyribose ring has been achieved using an aldolase-catalysed reaction with appropriately I3Clabelled DHAP/acetaldehyde substrates. The labelled sugar was then converted Carbohydrate Chemistry, Volume 34 0 The Royal Society of Chemistry, 2003 303
304
Carbohydrate Chemistry H
H?
H
O
Z
H
O 'H
,O
+
a
O 'H 1
croH F0
OH
2
EEpo3H2
i, ii
OH
W2)"
I O=P(OEt)2
_____L
(EQ2P
DHAP
Reagents: i, Fructose 1,&diphosphate aldolase; ii, Phosphatase scheme 1
II
-(CH2)"
OH 3 (n = 0,1,2)
to the O-protected ribosyl chloride prior to addition of the thymidine nucleobase." N-Hydroxypyrrolidine derivatives 6 has also been prepared (on a 2-3 g scale) by an E. coEi. transketolase-mediated reaction of (*)-3-O-benzyl glyceraldehydes 4 with hydroxypyruvate to set up the required stereochemistry on the trio1 building block 5 (Scheme 2).12 B
n
o 4
q
0
i
-
BnOO -H
__t
OH
5 (80%) Reagents: i, Transketolase, TPP, hydroxypyruvate, pH 7.0
I
OH 6
Scheme 2
2.2 Glycosidases. - Several reviews on the enzymatic preparation of glycosides and oligosaccharides using glycosidase-catalysed trans-glycosidation reactions have appeared.I3-l7Another review discusses the inulase-catalysedmass production of difructose anhydrides 7 and 8.18The a-glucosidase-catalysed reaction of maltose and glycerol has been shown to give a mixture of the three glyceryl a-D-glucoside regio-is~mers.'~ A hydrolytically inactive E358A mutant of an Agrobacteriurn sp. f3-glucan hydrolase has been used to construct P-lP-linked di-, tri- and tetrasaccharides 9 with a C-glycoside at the 'reducing' terminal end using a-D-glucopyranosyl fluoride donor and various g-C-glucosides as the 'reducing' end acceptor A new fbglucosidase from Thai rosewood has been shown to catalyse the synthesis of di- and tri-saccharides from glucose. The major di-saccharide product was gentiobiose, whilst starting from a mixture of D-fucose and D-glucose the main product obtained was @-~-Fuc-( 1-.6)-~G1c.21 A partially purified fi-glucosidase from Trichoderma uiride cellulase catalyses 1,6-transglycosylation reactions with cellobiose, laminaribiose and gentiobiose, but with poor yields?* Glycoside synthesis from aqueous starch solution and hydroxylbenzyl alcohols (0, rn and p), using amyloglucosidasefrom Rhizopus sp., has been shown to yield hydroxybenzyl a-glu~osides.~~ There have been two reports on the synthesis of novel hetero-branched g-cyclodextrins by
305
20: Enzymes in Mono- and Oligo-saccharide Chemistry
H HO
O
G
0
HO'
-
a
CH20H
e yH20H
OH
OH
OH
9 ( n = 0-2)
the reverse action of Aerobacter aerogenes pullulanase on fbcyclodextrin and various tri-/tetra-sa~charides?"~~ A comparative study of transglycosylation reactions using various newly cloned a-galactosidasesfrom B. stearothermophilus,Therus. brockianus, Streptococcus mutans and E. coli. has been carried out and all displayed the capacity for regioselective synthesis of a-(1-6)-disaccharides using a p-nitrophenyl f3-Dgalactopyranoside as donorF6The fl-gluco-/galacto-sidesof cis- and trans-2-pmethoxybenzyl cyclohexanol have been made using almond fl-glucosidase and f3-galactosidasefrom E. coli, respectively?' Transglycosylation of lactose using Streptococcus thermophilus led to 3'-f3-~-galactopyranosyl-lactose as the major product (16%), which was isolated on a 1 g scale?* The transglycosylating properties of a fbgalactosidase from Aspergillus aculeatus have been characterized using lactose as a substrate, and its activities towards exopolysaccharides from Lactococcus lactis have been ~tudied.2~ Cycloinulo-oligosaccharide fructanotransferase (CFTase)-catalysed decomposition of inulin in the presence of D-mannose and D-sorbose acceptors has been used to obtain inulotriosyl derivatives 10 and 11 on a preparative scale.30 Transfructosylation of 2-mercaptoethanol using sucrose and #J-fructosidases gives the S-glycoside product after long reaction times (20 h), whereas the O-glycosideaccumulates during shorter reaction times and then decays suggesting that the thioglycoside is relatively resistant to the hydrolytic action of the fructofuranosides? The formation and retention of cyclomaltodextrins inside starch granules has been achieved by reaction of cyclomaltodextrin glucanosyltransferase with solid granules.32There are also two reports on the use of cyclomaltodextrin-glucanosyltransferasein the preparation of pyridoxine 8glycosides, 12 and 13,from pyridoxin (vitamin B6)and maltode~trin.3~~~~ A bovine testes f3-galactosidase has shown a surprising lack of regiospecificity in f3-galactosylation of chito-oligosaccharides giving an equimolar ratio of terminal @-(1-4) and fl-( 1-3) galactosylated products.35The enzymatic synthesis of N-acetyl-lactosaminehas been investigatedwith a variety of galactose donors, cosolvents and fi-galacto~idases.~~ Pig liver fl-galactosidase has been used in
306
Carbohydrate Chemistry
OH
OH
'OH OH 10 R = a-D-mannos-l-yl 11 R = a-L-sorbos-1-yl
13
OH
p-(1+6)-disaccharide syntheses with p-nitrophenyl galactoside derivatives as donors and p-nitrophenyl glycosides of Gal, GalNAc and Glc as acceptors to obtain, for example, P-Gal-( 1-6)-a-Gal-OPNP and P-Gal-( 1-6)-P-GlcNAcOPNP. With P-D-galactosidase from Bacillus circulans the respective (1-3)linked disaccharides were obtained.37Both enzymes displayed a higher activity for a-glycoside acceptors. Regiospecific transglycosidic syntheses of P-Gal(1-4)-GlcNAc and a-NeuAc-(2-.3)-P-Gal-( 1-.4)-GlcNAc have been reported.38Galactosylation of 2-mercaptoethanol using P-galactosides from Penicillium multicolour or Aspergillus lorysae has been shown to give thioglycoside 14 as the major product (Scheme 3).39 +
HSCHzCH20H
YOH 14 major product
OH 15 minor product
Reagents: i, P-galactosidasesfrom various sources Scheme 3
P-D-G~c,a- and P-D-Man and P-Lac have been transferred from various donors to methanol and various glycosides and glycosyl fluorides by use of a crude filtrate from Thermoascus aurantiacus?' Synthesis of a-(1-2) and a-(1 4 3 ) linked disaccharides of mannofuranose using the reverse hydrolysis activity of partially purified a-mannosidases from almond meal (Prunus amygdalus) and limpets (Patella rulgatal) has been reported.41 Penicillium multicolour a - ~ fucosidase has been used to prepare a variety of 1,3-1inked fucose-containing disaccharides.42Fucosylated epitopes such as LeX and Lac(NAc)* have been prepared en~ymatically?~ Sugar oxazoline donors have been used in the chitinase-catalysed synthesis of GlcNAc-containing oligosa~charides?~ Incubation of Trichoderma reesei cellulase with xyloglycan or cellulose donors in an aqueous solution of various acceptor alcohols gave high yields of alkyl Pglyc0sides.4~ Concentrated plasticised glass mixtures of acceptors and donors have been shown to enable the glycosidase-catalysed syntheses of a functionally diverse
307
20: Enzymes in Mono- and Oligo-saccharide Chemistry
range of O-glycosides such as 16 and 17 at rates up to an order of magnitude greater than for dilute systems? There have been several reports on the sialidasecatalysed synthesis of a-sialylated oligosaccharides using a-NeuNAcOPNP as the don0r.4~,~~ Notably, various terminally sialylated di- and trisaccharides have been prepared by combination of sialidase-catalysed transglycosylation with polyethylene glycol o-monomethyl ether-based glycoside a~ceptors.4~
OH 16
17
OH
A novel thermophilic glycosynthase which effects branching glycosylation has been obtained by mutagenesis (D387G) of the active site nucleophile of a glycosidase from Sulfolobus solfaturicus, and by use of a-hexosyl fluoride donors and o- or p-nitrophenyl hexoside acceptors various di-, tri- and tetra-saccharides have been ~repared.~’ Another glycosynthase has been derived from Agrobacterium sp. p-glucosidase in a similar manner.51The synthesis of p-(1-.4)-oligosaccharides using a glycosynthase derived from Humicolu insolens, a-lactosyl fluoride and a variety of acceptors has been studied.52 2.3 Glycosyltransferases.- Three different transferases have been used in the chemoenzymatic synthesis of ‘bisecting-type’deca- and dodeca-oligosaccharides Dendritic polyethylene glycols have been used as of the bisecting-N-gly~ans.5”~~ soluble supports for acceptor substrates. For reactions which fail to reach completion the partially substituted support is recycled after simple dialysis, and treated with fresh enzymes and donors to improve the yields.55A range of Sa-carba-sugars, including both anomers of Sa-carba-~-GlcNAc18 (Scheme 4), have been tested as acceptors for p-(1+4)-galactosyl transferase-catalysed reactions with UDP-Gal as donor.56Isomers 18, which give 19, are the best acceptors of the compounds studied.
oq CH20H
CH20H @OH OH
@OH
i
NHAc 18 Reagents: i, UDP-Gal, galactosyl p-(1,4)-transferase Scheme 4
NHAc
OH
19
L-Glycosylamine derivatives 20 and 21 act as acceptor substrates for bovine
p-(1-.4)-galactosyltransferase which, surprisingly, catalyses transfer to the 3-
308
Carbohydrate Chemistry
hydroxyl groups.57The two human blood group A and B glycosyltransferases utilize UDP-GalNAc and UDP-GlcNAc donors, respectively. A hybrid enzyme A synthetic trihas been constructed that can utilize both these lactosamine has been further elaborated to sialyl-trimeric-L8 by enzymatic addition of the sialyl and fucose units.59Fucosyltransferase V only added two fucose units to the sialyl-tri-lactosamine precursor, whereas fucosyltransferase VI either completed the fucosylation or was used alone to put on all three fucose units. a-(l-.3)-Fucosyltransferase has also been used to transfer L-galactose moieties in the synthesis of a dimeric sialyl LeXanalogue.60
OH 20
OH 21
Recombinant hexa-histidine-tagged human a-(1-+3/4) fucosyltransferase I11 immobilized on nickel-agarose, exhibits marked stability which has been exploited in the synthesis of LeA and LeX trisaccharides with the enzyme still retaining 50% activity after a 10 day incubation at 37 0C.61Fucosyltransferase I11 has also been used to prepare glycal derivatives of SiaLeX.62 Studies of a 2,3sialyltransferase(v-ST3Gal I), obtained from myxoma virus infected RK13 cells, have revealed its unique substrate specificity amongst previously characterized sial~ltransferases.6~ In addition to catalysing sialyl transfer from CMP-NeuAc to type I, I1 and I11 acceptors, this viral enzyme also transfers sialic acid to the fucosylated acceptors LeXand LeA.UDP-Glucuronyltransferases from ~ v i n e ~ ~ and human liver micro some^^^ have been used to prepare lysergol fl-D-glUCUrOnide and 3-0-benzylmorphine-6-glucuronide, respectively. An intein-mediated protein ligation strategy has been used to incorporate glycopeptides 22 at the C-terminus of proteins, and the GlcNAc unit of the ligation product 23 served as a substrate for subsequent fl( 1+-4)-galactosyltransferase- catalysed modification (Scheme 5).66
H
0 C02H NHAc 22 UDP-Gal UDP Reagents: i, Galactosyl p-(1,4)-transferase Scheme 5
OH
23
2.4 Lipases and Acyl Transferases. - A recent review of synthetic applications of enzymes in organic solvents details examples of lipases and proteases exploited in the chemoenzymatic O-substitution of sugar derivative^.^^ Lipase from Hurnicola Eanuginosa, together with various vinyl esters, has been used for specific and high yielding (70-90%) 6-O-acylation of the non-reducing-terminal glucose moieties of maltose, maltotriose and dodecyl a,P-maltosides.6* A mixture of
309
20: Enzymes in Mono- and Oligo-saccharide Chemistry
1,3,4-t~deoxy-5,6:7,8-di-O-isopropylidene-~-~-mannoand gluco-non-5-ulo-5,9pyranose [(R,S)-24] have been separated by stereoselective acylation using vinyl acetate and Chirazyme@L-2 to give the manno-acetate 25 (Scheme 6).69
I
(R,S)-24 Reagents: i, Vinyl acetate, ChirazymeB L-2
T"
OAc 25
26
Scheme 6
Lipase from Candida antartactica has been used in the preparation of various acylated maltooligosaccharides,'o ascorbic acids,71disaccharides7*and human milk trisa~charides~~ and also for the regioselective 1,6-co-polymerization of D-glucitol and di-vinyl ~ e b a c a t eA . ~novel ~ aminoglycoside 6'-acetyltransferase from Actinomycete sp. has been used for the acetylation of a large selection of aminoglycoside antibiotic^.^'*^^ A Pseudumunas lipase on ceramic particles and on diatomite has been used to regioselectively acylate nucleosides and 2'deoxynucleosides at 0-3' by transfer from various 0-acetyl aldehyde or ketone oximes in 70-90% yields.77 Chitin deacetylase has been used in the synthesis of partially and fully N deacetylated 4-methyl umberlliferyl chitobiose derivatives as fluorogenic substrates for ~ h i t i n a s e .Conversely, ~~ the reverse acylating action of chitin deacetylase has been used to prepare a partially N-acetylated chitosamine tetramer.79The preparation of a 4-0-acetyl sialic acid derivative by a lipase OF-catalysed deacetylation of the peracetylated precursor has been reported.80 Regioselectively protected cytidine derivatives have been prepared from the peracetylated nucleoside using lipase and esterase reactions." There have been reports on the use of bacterial proteases for the selective acylation of sucrose to produce a variety of different acyls2and acrylate esters.838-Aminooctyl 5-Sconiferyl-5-thio-a-~-arabinofuranoside (27)attached to sepharose proved to be a selective affinity ligand for feruloyl esterase A. n i ~ e r . ~ ~
2.5 Sulfotransferases. - A recent study of keratan sulfate Gal-6-sulfotransferase (KSGal6ST) has demonstrated its ability to sulfate 0 - 6 of the Gal residue of NeuAc-(2+3)-fbGal-( 1+4)-GlcNAc (3'SLN), fetuin oligosaccharides and their desialylated derivatives? The relative sulfation rate of some of the compounds was much higher than for keratan sulfate.
2.6 Coupled, Multi-Enzymatic and Whole Cell-based Syntheses. - A recent review discusses preparations of antiviral nucleosides by the sequential use of
310
Carbohydrate Chemistry
nucleoside phosphorylase and N-deoxyribosyltransferase enzymes.86A detailed review of the integration between the enzymatic epimerization of GlcNAc to nNAc and the NeuSAc aldolase-catalysed bio-transformation to NeuSAc has been reported.87Wong has reviewed complex carbohydrate synthesis tools that are accessible to glycobiologists, with particular focus on enzymatic and computer based one-pot approaches for the preparation of complex carbohydrates/glycoconjugates.88 The tetra-saccharide p-D-Gal-(1-.4)-P-~-GlcNAc-( 1-3)-P-~-Gal-(1 4 ) - G l c has been made by three methods of increasing efficiency: (i)conventional organic synthesis, using a lactose acceptor (30%);(ii) similarly with an MPEG-supported lactose acceptor (53%); (iii) enzymatically (96%).89A sequential one-pot synthesis of UDP-2-deoxy-2-fluoro-~-ga~actose from D-galactal using selectfluoride, galactokinase and galactose- l-phosphate uridyltransferase has been reported.” The five per-O-acetylated disaccharide glycones of 28-32, structurally related to the glycans of vertebrate mucins, have been evaluated for their ability to prime oligosaccharide synthesis, inhibit glycoprotein synthesis and alter adhesion to E-selectin expressed in endothelial cells. All these compounds served as substrates for the enzymic synthesis of oligosaccharides?’ 28 Gal+( 1-4)-GlcNAc-P-OR 29 GlcNAc-P-(1-3)-Gal-P-OR 30 Gal+( 1-3)-GalNAc-a-OR 31 GlcNAc-P-(1-3)-GalNAc-P-OR 32 GlcNAc-P-(1-6)-GalNAc-P-OR
A preparative synthesis of GDP-P-L-fucose from GDP-D-mannose using recombinant enzymes from enterobacterial sources has been achieved?2The enzymatic conversion of D-glucose to nucleotides by the stepwise addition of sequential enzymes in the glycolytic and pentose phosphate pathway has been used for the preparation of 2H- and l3C-labe1led RNA.93TDP-3,6-dideoxy-P-~-arabinohexopyranose has been produced on a 200 mg scale from TDP-3-deoxy-a-~glucose by the L-rhamnose synthesizing system isolated from Salmonella entericum LT2.94Various 13C-labelled4-O-diphosphocytidyl-2-C-methyl-~-erythritols have been prepared from sodium pyruvate and labelled D-glucose in a one-pot procedure by use of a mixture of five recombinant enzymes from the nonmevalonate isoprenoid p a t h ~ a y ?The ~ uptake of a 12-azidododecyl p-lactoside primer for sialylation by B16 melanoma cells resulted in the 3’-glycosylation product which is a glycoside of ganglioside GM3.96 A one-pot, two-step enzymatic 13C-labelling method for the preparation of sialic acid analogues 35 has been developed (Scheme 7)?7 Multi-enzyme approaches have been used to prepare bisecting-type oligosaccharides from bisecting-N-glycan saccharide~.~~ The lipophilic benzyloxycarbonylaminoaniline group has been used to derivatize reducing oligosaccharides, to give products such as 36 following N-acetylation, which can be further elaborated by multistep enzymatic glycosylation. The lipophilic moiety enables facile purification by C 18 reverse phase chromatography after each reaction? The UDP-2- and
311
20: Enzymes in Mono- and Oligo-saccharide Chemistry
L
"*CO2H
NeuAc aldolase T
*
- - OH
AcHN
Ho' 33 Cofactor regeneration OH
R j = H, OH, N3, F R2 = H, OH R3 = H, OH
I
0
LUH
A C 0 2 H L-lactic acid
/
IJ- NADH
\
ACOzH Pyruvic acid
2
g
(i) NPP
Addition of [3-'3C]-pyruvicacid after inactivation of LDH
acetaldehyde LDH: L-lactate dehydrogenase ADH: alcohol dehydrogenase NPP: nucleotide pyrophosphatase
*'AcHN HO 35 = I3c
Scheme 7 CH20H
OH
C02H
0
36
3-fluorogalactopyranose sugar nucleotides have been prepared from 2- and 3-deoxy-2- and 3-fluoro-~-galactoseusing a one-pot cocktail of nine commercial en~ymes.9~ Both these compounds were used as mechanistic probes for UDPGalp-mutase. Starting from UDP-Glc, a variety of a-mGal-(1+4)-P-~-Galderivatives have been prepared using a UDP-Glc-4-epimerase-a-l,3-Gal-transferase fusion enzyme. The fusion protein enhanced reaction rates by 300% compared to the same reactions carried out with equivalent amounts of the two separate enzymes." A one-pot route to ketoses, such as 38, from glycerol and pyrophosphate, via their phosphorylated precursors 37 has been developed using phytase (Scheme 8).lo' Glycopeptides derived from P-selectin glycoprotein PSGL- 1 have been prepared from peptidic disaccharide precursors using the appropriate glycosyl transferases.lo2Manipulation of the biosynthetic machinery in Streptornyces venezuelae, which normally produces macrolides containing D-desosamine, has resulted in L-rhamnose being appended instead.'O3A GlcNAc kinase gene (yqgR) from Bacillus subtilis has been added to a yeast-based reaction system to improve the whole cell synthesis of UDP-G~CNAC.'~
312
Carbohydrate Chemistry pyrophospitate H O A OH O P 0 3 H 2
h%
+
HO&OH
?H
H O A O P O 3 H 2
I
Four steps, one pot
I
3
OH
0
1
Enzyme Mechanisms
A review of glycosidase mechanisms has recently appeared, which primarily deals with the hydrolytic mechanisms of ~-glucosidases.105 Two other review papers cover a broad range of novel enzymatic mechanisms in carbohydrate metabolism such as epimerase reactions, 1,2-carbonyl rearrangements (e.g. with D-xylose isomerase), C-0 bond cleavage reactions (excluding glycosidases),C-C bond formation in branched chain sugars and reactions involved in the formaA review of tion/rearrangement of hexose skeletons (e.g. DHQ syntha~e).'~*'~' mechanism-based inhibitors of Kdo8P synthase has also appeared (see Chapter 16).'08 Photoreactive aryl glycosides bearing an azido, a diazonium salt or a diazirine substituted aryl group as the photoprobe have been developed to study the sugar binding site of melbiose p e r m e a ~ e .All ' ~ ~possible monomethyl ethers of p-nitrophenyl a-D-gluco-, a-D-galacto and a-D-mannopyranosides have been made and used to evaluate the hydrolytic activities of various glycosidases. Mortierella vinacea a-galactosidase and almond and jack bean a-mannosidases were found to hydrolyse the glycosidic bonds of the respective 6-0-methyl ether derivatives whereas the other monomethyl ethers were unreactive.'" The substrate properties of the 2-, 3-, 4- and 6-deoxy-a-~-galactopyranosidesof p-nitrophenol have been studied with a-galactosidases from several sources. The 3-, 4- and 6hydroxyl groups were essential for some of the enzymes, and the 2-deoxyglycoside was a substrate for all the enzymes studied."' 5-Deoxy+fluoro-a-~galactosyl fluoride has been prepared and used to trap an intermediate of green
20: Enzymes in Mono- and Oligo-saccharide Chemistry
313
coffee bean a-galactosidase reaction in order to identify the catalytic aspartate nucleophile.' l 2 The glycosidase-catalysed hydrolysis of isoquinolinium salts 39 and 40 have been st~died."~Bothare enzyme substrates, but 39 binds more tightly to the enzyme than does the 2-deoxy compound 40, and the enzymecatalysed hydrolysis rate of the former is 104times higher. The authors concluded that the interaction of the 2-OH group with the a-glucosidase generates a relative transition state stabilization of about 23.5 kJ mol-'.
39 R = O H 40 R = H
41 n z 0 - 2
l-O-(p-Hydroxybenzoyl) @-galactosewas synthesized to examine the hydrolytic activity of the p-galactosyl ester linkage by fbgalactosidases. Of particular interest, the enzyme from Penicillium multicolor hydrolysed this substrate in the presence of 180-labelledwater to liberate galactose containing l 8 0 suggesting that C - 0 bond cleavage occurs at the anomeric carbon rather than the ester carbonyl carbon ~entre.''~ A computational method has been presented for predicting the alcohols which can be glucosylated with ~-glucosida~es.'~~ Experiments with p-nitrophenyl f3-D-fucofuranosidehave shown it not to be a substrate for the exo-p-D-galactofuranosidasefrom P. fellutanum which indicates that the C-6 hydroxyl group is essential for activity.'16'H NMR spectroscopy has been used to investigate the transfer of sialic acid from donor to acceptor molecules using trans-sialidase from T. cruzi."' A separate study of this enzyme by 'H NMR has shown that its stereoselectivity is identical to that of bacterial, viral and mammalian sialidases, suggesting a similar active-site architechture.' l 8 The action pattern of human salivary amylase (HSA) has been examined by HPLC analysis of the product pattern and cleavage frequency of model maltooligosaccharides of dp 4-8.'19 Results suggest the binding region in HSA is longer than the five subsites usually considered in the literature, and imply differences between the 3D structures of HSA and porcine pancreatic a-amylase. The 2', 3' and 4'-modified deoxy and O-methylfucopyranose derivatives of a-L-Fucp(1-2)-fb~-Galp-l-O-octyl have been made as acceptor analogues for the human blood group A and B Gal- and GalNAc-transferases. Experiments with all these compounds have shown that the 2'-OH is an essential feature for recognition by these enzymes.'2oBoth enantiomers of 1,2-anhydro-myo-inositol have been prepared and assessed as glycosidase inhibitors. The l-D-isomer was shown to be active against 6-glucosidase but neither isomer was active against a-glucosidase or P-galactosidase.'21A series of C-4' branched deoxynucleotides 41 have been prepared and incorporated into oligodeoxynucletidesthe resistance of which to snake venom phosphodiesterase and DNAase is notably increased by the modifications.'22 NMR studies have shown that the conformation of D-gluco-dihydroacarbose
314
Carbohydrate Chemistry
bound in the active site of glucoamylase resembles that found in the crystal structure rather than the unbound solution conf~rmation.'~~ Both a-fluorophosphonate analogues of glucose 6-phosphate have been made and studied as substrate mimics for glucose 6-phosphate dehydrogenase. Surprisingly, the kcat/&, value of the 7(S)-diastereomeris an order of magnitude greater than that of the 7(R)-diastereomer,which is explained in the context of the known phosphate binding pocket of this enzyme.'24
4
Other Enzymatic Modifications
An extensive review on the chemoenzymatic radiolabelling of gangliosides has been r e ~ 0 r t e d . lTritium ~~ labelling has been achieved by C-6 oxidation of the galactose moieties using galactose oxidase [EC 1.1.3.91 followed by chemical reduction of the aldehyde products with tritium-labelled sodium borohydride. The selective biocatalytic modifications of conventional, carbocyclic and Cnucleosides have also been reviewed.126L-Rhamnose isomerase of Pseudomonas sp. LL172 immobilized on Chitopearl beads has been used to produce L-talose and D-gulose from L-tagatose and D-sorbose, re~pective1y.l~~ Eleven synthetic D-glucuronans have been epimerized to varying extents with Azobacter vinelandii poly-p-D-mannuronic acid C-5-epimerase to give copolymers of D-glucuronic acid and L-iduronic acid with different viscocities, acid susceptibilities and capacity to form calcium-gels which were compared with those of the unepimerized D-glucuronans.'28 An enzyme involved in the biosynthesis of the 4-epivancosamine substituents of a vancomycin group antibiotic has been expressed and its role as a TDP-4-keto-6-deoxyglucose-3,5-epimerase has been dem0n~trated.l~~ The stereo-/regio-specific syntheses of Gal$-( 1+3)-GlcNAc derivatives using the ~-1,3-galactosyl-N-acetylhexosamine phosphorylase enzyme from BiJidobacterium bijidum DSM 20083, which catalyses the reversible phosphorolytic cleavage of p-(1-.3)-galactooligosaccharides, have been re~0rted.l~' The preparation of 2'-deoxyribonucleosides with identically 2H/13Clabelled sugar residues has been achieved by the enzymatic transglycosylation reactions of purine/pyrimidine nucleoside phosphorylases with isotopically labelled thymine (the preparation of which is described in Chapter 19).I3l Sucrose phosphorylase from Leuconstroc mesentroides has been used for the enzymatic transglucosylation from sucrose to 4-hydroxy-3(2H)-furanone derivatives in the preparation of potential antioxidant compounds 42 and 43.132A
42 R' = Me, R2 = Et 43 R' = Et, R 2 = Me
315
20: Enzymes in Mono- and Oligo-saccharide Chemistry
procedure for the preparation of GMP using guanosine-inosine kinase from Exiguobacterium acetylicum coupled with ATP regeneration has been reported.'33 A range of fluoro- and/or azido-derivatives of D-fructose have been prepared by the polyol dehydrogenase catalysed isomerization of the corresponding D-glucose s ~ b s t r a t e s . ' ~ ~ An efficient double oxidation of D-xylose to ~-glycero-aldopentos-2,3-diu~ose (2,3-diketo-~-xylose,45) has been achieved (80% yield) using pyranose dehydrogenase from the mushroom Agaricus bisporus (Scheme 9).135The gram scale 2'-deoxygenation of ATP has been achieved using a recombinant ribonucleoside triphosphate reductase from Lactobacillus lei~hrnannii.'~~ OH OH
OH
O
5
O
0
BQ HQ BQ = o-benzoauinone HQ = hydroquinone
Reagents: i, Pyranose dehydrogenase
R
H
*HoQoH
BQ
HQ
0 45
44 Scheme 9
Miscellaneous
A potential two-step process to convert D-glucose to catechol(48) via D-glucose6-phosphate (46) has been developed. This comprises a one-pot incubation of the sugar with hexokinase and recombinant 2-deoxy-scyllo-inosose synthase, followed by chemical reductive dehydration of the resulting 2-deoxy-scyllo-inosose 47 with hydrogen iodide (Scheme
OH 47 (68%) Reagents: i, Hexokinase; ii, 2-deoxy-scyllo-inososesynthase; iii, HI, HOAc Scheme 10 OH
46
OH
48 (59%)
Various phosphorylated pentose derivatives (e.g. D-arabinose 5-phosphate, 49) have been condensed with mono-deuterated ( Z ) and (E)-phosphoenolpyruvates in the presence of E. coli 3-deoxy-~-arabino-heptulosonate 7-phosphate (DAH 7-P) synthase. The products were in complete agreement with the observed facial selectivity of DAH 7-P synthase with its native substrates (Scheme 1l).138 0
OH
(HO)zko+o
OH OH 49 Reagents: i, DAH 7-P synthase
HzHz;zTH)2
0 II
HE
i
k OPOSH~
C02H
HO
50
Scheme 11
OH
3 16
Carbohydrate Chemistry
A nonmevalonate pathway intermediate, 4-(cytidine 5'-diphospho)-2-Cmethyl+-erythritol is transformed to its 2-phospho-derivative in the presence of ATP by a novel E . coli enzyme, 4-(cytidine 5'-diphospho)-2-C-methyl-~-erythritol k i n a ~ e .The ' ~ ~ same authors report the enzymatic conversion of this product to 2-C-methy~-~-erythritol2,4-cyclodiphosphate using a cyclodiphosphate synthase isolated from the same source.14oWaldmann et al. have reported the use of the tetra-0-acetyl gluco-/galactopyranosyl oxycarbonyl unit as an N-terminal peptide protecting group. a/P Mixtures of the resulting carbohydrate-derived urethanes, e.g. 51, are readily cleaved in a one-pot procedure involving enzymatic deacetylation followed by glycosidase-catalysed glycosidic bond fragmentation (Scheme 12).14' H N -Ala-Gly-OBu'
&--OK OAc
I
II
i, ii
* H2N-Ala-Gly-OBu' + Glucose
n
51 Reagents: i, Lipase WG, 5% MeOH, pH 6.0; ii, alp glucosidase
Scheme 12
Various dermatan sulfate derived di-, tetra-, hexa-, octa-, deca- and dodecasaccharide mixtures have been prepared and purified (on a semi-preparative scale) by controlled depolymerization of dermatan sulfate using chondroitin ABC 1ya~e.l~' The pathways of InsP6 hydrolysis by phytase from wheat bran of Triticum aestivum have recently been e~tab1ished.I~~ An improved ( x 10) method for assaying a-glucosidases has been developed using aryl P-maltosides as substrates with P-glucosidase as an auxiliary enzyme.lM
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Carbohydrate Chemistry
106. X.He, G. Agrihotri and D.-W. Lui, Chem. Rev., 2000,100,4615. 107. D.A. Johnson and H.-W. Liu, Biol. Chem. Interjace, 1999,351 (Chem. Abstr., 2000, 132,108 160). 108. T. Baasov and V. Belakhov, Recent Res. Deuel, Organic Chem., 1999,3,195 (Chem. Abstr., 2000, 132,249). 109. Y. Ambroise, C. Mioskowski,G. Leblanc and B. Rosseau, Bioorg. Med. Chem. Lett., 2000,10,1125. 110. W. Hakamata, T. Nishio, R. Sato, T. Mochizuki, K. Tsuchiya, M. Yasuda and T. Oku, J. Carbohydr. Chem., 2000,19,359. 111. W. Hakamaya, T. Nishio and T. Oku, Carbohydr. Res., 2000,324,107. 112. H.D. Ly, S. Howard, K. Shum, S. He, A. Zhu and S.G. Withers, Carbohydr. Res., 2000,329,529. 113. K.S.E. Tamaka, J. Huang, F. Lipari and A.J. Bennet, Can. J. Chem., 2000,78,577. 114. T. Kiso, H. Nakano, H. Nakajina, T. Terai, K. Okamoto and S. Kitahata, Biosci. Biotechnol. Biochem., 2000,4,1702. 115. B.M. de Roode, H. Zuilhof, M.C.R. Frannsen, A. Nan du Padt and A. de Groot, J . Chem. Soc. Perkin Trans. 2,2000,2217. 116. A. Chiocconi, C. Marino and R.M. de Lederkremer, Carbohydr. Res., 2000,323,7. 117. J.C. Wilson, M.J. Kiefel, S. Albouz-Abo and M. von Itzstein, Bioorg. Med. Chem. Lett., 2000,10,2791. 118. A.R. Todeschini, L. Mendorca-Previatol, J.O. Previato, A. Varki and H. van Halbeek, Glycobiology, 2000,10,213. 119. L. Kandra and G. Gyemant, Carbohydr. Res., 2000,329,579. 120. A. Mukherjee, M.M. Palcic and Q. Hindsgaul, Carbohydr. Res., 2000,326,l. 121. A. Falshaw, J.B. Hart and P.C. Tyler, Carbohydr. Res., 2000,329,301. 122. M. Kanazaki, Y. Ueno, S. Shuto and A. Matasuda, J. Am. Chem. Soc., 2000, 122, 2422. 123. T. Weimar, B.O. Petersen, B. Svensson and B.M. Pinto, Carbohydr. Res., 2000,326, 50. 124. D.B. Berkowitz, M. Bose, T.J. Pfannenstiel and T. Doukov, J . Org. Chem., 2000,65, 4498. 125. S. Sonino, V. Chigorno and G. Tettamanti, Methods Enzymol., 2000,311,639. 126. M. Ferreo and V. Gotor, Chem. Rev., 2000,100,4319. 127. S.H. Bhuiyan, Y. Itami, G. Takada and K. Izumori, J. Biosci. Bioeng., 1999,88,567 (Chem. Abstr., 2000,132,222 721). 128. P.S. Chang, R. Mukerjea, D.D. Fulton and J.F. Robyt, Carbohydr. Res., 2000,329, 913. 129. P.N. Kirkpatrick, W. Scaife, T.M. Hallis, H. Lui, J.B. Spencer and D.H. Williams, Chem. Commun., 2000,1565. 130. E. Farkas, J. Thiem, F. Krzewinski and S. Baiquelet, Synlett, 2000,728. 131. Y. Oogo, K. Nonaka, A. Ono, A. Ono and M. Kainosho, Nucleic Acids Symp. Ser., 1999,42,123 (Chem. Abstr., 2000,132,279 443). 132. S. Kitao, T. Matsudo, T. Sasaki, T. Koga and M. Kawamura, Biosci. Biotechnol. Biochem., 2000,64,134. 133. H. Kawasaki, Y. Usuda, M. Shimoaka and T. Utagawa, Biosci. Biotechnol. Biochem., 2000,64,2259. 134. P. Hadwiga, P. Mayr, B. Nidetzky, A.E. Stutz and A. Tauss, Tetrahedron Asymm., 2000,11,607. 135. J. Volc, P. Sedmera, P. Halada, V. Prikrylova and D. Haltrich, Carbohydr. Res., 2000,329,219.
20: Enzymes in Mono- and Oligo-saccharide Chemistry
321
136. A. Brunella, M. Abantes and 0. Ghisalbe, Biosci. Biotechnol. Biochem., 2000,64, 1836. 137. K. Kakinuma, E. Nango, F. Kudo, Y. Matsushima and T. Eguchi, Tetrahedron Lett., 2000,41,1935. 138. A.K. Sundaram and R.W. Woodard, J. Org. Chem., 2000,65,5891. 139. T. Kuzuyama, M. Takagi, K. Kaneda, H. Watanabe, T. Dairi and H. Seto, Tetrahedron Lett., 2000,41,2925. 140. M. Takagi, T. Kuzuyama, M. Takagi, K. Kaneda, H. Watanabe, T. Dairi and H. Seto, Tetrahedron Lett., 2000,41,3395. 141. A.G. Gum, T. Kappes-Roth and H. Waldmann, Chem. Eur. J., 2000,6,3714. 142. H.O. Yang, N.S. Gunay, T. Toida, B. Kuberan, G. Yu,Y.S. Kim and R.J. Linhardt, Glycobiology, 2000,10,1033. 143. T. Nakano, T. Joh, K. Narita and T. Hayakawa, Biosci. Biotechnol. Biochem., 2000, 64,995. 144. Y.V. Voznyi, I.S. Lukomskaya, I.M. Lanskaya and E.I. Podkidysheva, Vopr. Med. Khim., 1996,42,348 (Chem. Abstr., 2000,132,237 265).
21
Structural and Quantitative Analytical and Separatory Methods
1
Computational Methods
An extensive review on structures, configurations and dynamics of bioactive oligosaccharides included a section on computational studies.' Improvements in the quantum mechanical calculations of the potential energy surfaces of D-aldohexoses and D-ketohexoses have been reported.2 The relative reactivities of the free hydroxyl groups in the partially protected methyl 4,6-0benzylidene-a- and P-hexopyranosides 1 (D-ab-, D-galUCtU-, D-gluco- and Dmanno-configuration) have been explored by conducting experiments with the molecular modelling program STR3DI.EXE and its molecular mechanics module QVBMM.3 Conformational energy maps for the furanosyl and pyranosyl rings of ribose and 2-deoxyribose in solution, generated with the MM3 force field, indicated the presence of several tautomers in multiple conformations for both compound^.^ The preferred conformations and energy pseudorotational barriers of 2-deoxyP-D-ribofuranosylamine in protonated and unprotonated form have been established by use of ab initio molecular orbital and density functional theory calculat i o n ~ Three-, .~ two- and one-bond 'H-I3C spin coupling constants in anhydrodeoxythymidines have been determined both by ab initio calculations and by NMR experimenh6 Modelling experiments have been undertaken to compare the conformations of the seven-membered ring aza-sugars 2 (see Chapter 18 for synthesis), with those of DNJ and i~ofagamine.~ Further monosaccharide pyranosyl compounds to have been investigated by use of computational techniques were the anticancer agent etoposide in CD30D, dry CDC13 and wet CDC13,8 and a series of ellagitannin models with axial chirality in the hexahydroxydiphenoyl moieties, such as compound 3.9 Modifications have been made to the AMBER force field to improve the correlations between calculated and observed molecular properties of a-linked saccharides;'O these led to refinements in solvation studies on maltose, a-, fland y-cyclodextrin and two larger cyclodextrins (DP 10 and 21)." A molecular dynamics simulation investigation of the solvation patterns of the model disaccharide 4 in aqueous DMSO defined regions in which competition exists Carbohydrate Chemistry, Volume 34 0 The Royal Society of Chemistry, 2003
322
323
21: Structural and Quantitative Analytical and Separatory Methods CH20H
l
H
HO G
Ho
1
-
-
Hd
OH
O
o
H
,OH
OH
between the solvents, whereas other parts of the molecule were preferentially solvated by one solvent.’* a-D-Manp-(1+3)-P-~-GlcpOMe
4
The decisive role of the exo-anomeric effect in the conformational behaviour of interglycosidic linkages has been demonstrated by molecular dynamics and molecular mechanics studies on the preferred solution conformations of eight C-linked D-glucosyl disa~charides,’~ of the C-linked disaccharide 5 together with its natural 0-linked equivalent 6,14and of the two isomeric hydroxymethylenelinked analogues of sialyl-a-(2+3)-~-galactose.’~
-
a-X-D-Manp-( 1 l)-P-D-Galp 5X=CH2 6X=O
The preferred solution conformations of a number of glycosyl myo- and chiro-inositols,e.g. compounds 7 and 8, that are potential mimics of the putative inositolphosphoglycan mediators (IPGs), have been examined by computational methods as well as NMR spectroscopy.16 OR2
OR2 R
’
O
A ,OR2
9
2
Spectroscopy
The Pr(I1) and Nd(II1) complexes of three pentoses, three hexoses and two disaccharides were characterized by various spectral and analytical techniques including FT IR, 13CNMR, solution absorption and solid-state diffused reflectance spectroscopy, magnetic susceptibility and CD measurements, as well as cyclic voltammetry and thermal analysis.”
324
Carbohydrate Chemistry
2.1 NMR Spectroscopy. - Several extensive reviews on the use of ‘H and 13C NMR spectroscopy in the carbohydrate field have been published. One addressing the general problem of structural assignments of complex carbohydrates covered traditional as well as new NMR techniques including computer-assisted evaluation of spectra,’* another one focussed on blood-group oligosaccharides, Lewis X, sialyl Lewis X, fragments of glycosaminoglycans and structural oligosaccharide mimetics.’ A third one dealt with the use of stable isotopes (I3C, 2H)in conjunction with NMR spectroscopy in the evaluation of carbohydrate structure, conformation and reactivity.” An essay entitled ‘NMR of Carbohydrates, Lipids and Membranes’ highlights the application of contemporary NMR techniques to solving microbiological, industrio-pharmaceutical and biomedical problems.20In a review on recent advances in the 0-sialylation of saccharides the NMR criteria for the anomeric assignment of sialosides are summarized.2l
2.1.1 Technique. Mixtures of sugars with the same molecular weight (e.g. Darabinose and D-ribose), as well as tautomeric forms of a single sugar (e.g. a-D-ribofuranose, fbmribofuranose, a-D-ribopyranose and P-D-ribopyranose) have been distinguished by diffusion-ordered NMR spectroscopy (DOSY) in the presence of lanthanide cations. This significant development is based on the different diffusion rates of complexed and non-complexed species.22A new, one-dimensional 13CNMR approach for determining the configuration of 0methyl substituents in glycosides by use of non-refocussed INEPT experiments associated with numerical methods has been New procedures for suppressing the interfering methylene signals of protecting groups, such as those of benzyl ethers and cyclohexylidene acetals, in 2D NMR spectra of 01igosaccharides,2~and for eliminating spin diffusion effects from NOE mea~urements~~ have been established. A new strategy to overcome resonance overlap involving 3D-TOCSY and transfer-NOE experiments has been employed for the unambiguous identification of bioactive ligands in product mixtures; as an example, a library of fifteen mono-, di-, and tri-saccharides was successfully screened for compounds that bind specifically to Aleuria aurantia agglutinin.26 The active site of KDO 8-phosphate synthase complexed to its natural substrate and to an inhibitor has been identified by use of rotational-echo doubleresonance (REDOR) solid state NMR spectro~copy.2~ 2.1.2 Conformational and Structural Analysis. Detailed ‘H NMR spectroscopic studies of hydrogen bonding in selected monosaccharides and inositols,28as well as in selected di- and oligo-saccharides (cellobiose, lactose, N,N’-diacetylchitobiose, agarose, etc.):’ in CDC13 and DMSO-d6 revealed that discriminations can be made between intra- and inter-molecular hydrogen bonds, between weak and strong intramolecular hydrogen bonds and between hydroxyl groups acting as donors and acceptors. Simple formulae or rules for approximating &(OH) of fully solvated secondary hydroxyl groups of monosaccharides in DMSO have been developed. Restricted conformational freedom associated
21 :Structural and Quantitative Analytical and Separatory Methods
325
with persistent C(3)-OH * - * O-C(5’) bonds was detected in a number of disaccharides, for example in cellobiose (9), lactose and N,N’-diacetylchitobiose. By use of similar techniques, inter-residue hydrogen bonding has also been observed in disaccharides 10 and 11,30but in the case of the Lewis b tetrasaccharide derivative 12 no evidence was found for persistent hydrogen bonds participating in the structural stabilization?1 p-~-GlcpNAc-( 1-.4)-fk~-GlcpNAc p-~-Galp-( 1+3)-a-~-GalpNAc-OMe 10 11 a-L-Fucp 1
s.
6
a-~-Fucp-( 1-+2)-p-~-Galp-( 1~~)-~~-D-G~C~NAC-O(CH~)~NHCOCHC 12
A study on intramolecular hydrogen bonding in N-(2-amino-2-deoxy-fb~glucopyranosy1)-N-carbamoyl-L-dipeptidylester focussed mainly on the conformations of the peptide 2.1 -2.1 Monosaccharides. Erythro-Hexo-2,5-diulose has been shown by ‘H NMR spectroscopy to exist as a mixture of the acyclic and the four pyranose forms in DMSO. In water, three furanose forms and four hydrated pyranose forms were also present.33 A variety of NMR spectroscopic methods have been applied to structural and conformational analyses of the following furanose systems: sugar gern-dimethyl substituted alkenyl ethers, e.g. a-D-xylofuranose derivatives 13 (see Chapter 5 for ~ynthesis)?~the diastereomeric 6-chloro-6-deoxy-l,2-O-isopropylidene-a-~gulofuranose cyclic 3,5-piperididomonophosphates 14,35several 4-thionucleo6-formyl- and 6-(hydroxymethy1)-uridine5’-carboxaldehydes 15 and 16, respectively, and their 2’,3’-O-isopropylidene derivative^?^ two 13C-2Hdoublelabelled 2’-deoxynucleosides complexed to deoxycytidine kina~e,~* and various nucleoside 5‘-triphosphates (AZTTP, dTTP and dATP) bound to HIV-RT in the ground state, i.e., prior to the conformational changes to form catalytic com~ l e x e sThree-, . ~ ~ two- and one-bond ‘H-I3Cspin coupling constants in anhyd2,5’-anhydro-l-(2’-deoxy-P-~rodeoxythymidines (2,3’-anhydroand furanosy1)thymine)have been determined both by NMR experiments and by ab initio calculations.6 The H-C(1)-C(2)-Htorsion angles of a- and f3-D-glucopyranoseand of methyl a-D-glucopyranoside in the crystal as well as in solution have been calculated on the basis of double-quantum heteronuclear local field NMR experiments using [1,2-13C2]-D-glucopyranose and methyl [1,3-13C2]-a-~-glucopyranoside.~ Mono- and di-fatty acid esters of a-D-glucopyranose have been characterized on the basis of the substituent-induced chemical shift effects on the carbonyl carbon atoms.‘“ The chiralities at sulfur in epimeric sulfenyl glycosides, obtained by mCPBA oxidation of the corresponding ethyl 1-thio-p-glycopyranosides, were readily
326
Carbohydrate Chemistry
determined from NMR spectral data, since under the influence of the exoanomeric effect the minor R,-isomers, such as 17, assume the preferred conformation shown, giving rise to very large (2170 Hz) differencesin the chemical shifts of and Hpro-~:2 Further monosaccharide pyranosyl compounds to have been investigated by NMR spectroscopic methods included a-and (3-~-idopyranoseP~ methyl 2,6:3,4dianhydro-a-D-altropyranoside (18),44methyl D-glucopyranuronate derivatives 19,45ellagic acid derivatives of D-xylose and D-glucose,46 the anticancer agent etoposide in CD30D,dry CDC13and wet CDC13,' the major and minor conformational isomers (owing to restricted rotation about the amide bond) of the rare alkaloid casimiroedine (20) and its pera~etate;~and the diacylmannosylerythritois 21.48
OH OH 15 R=CHO 16 R = CH20H
13 R = O T r o r H
C02Me
OMe 18
OAc 19 R' = H, R~ = OH or R' = OAII, R~ = H
H CH20R2
R 2 40
OH
Z
V
I
O OH H CHzOH
20
21 R' = C(0)(CH2),Me, n = 6-10; R2 = H or Ac CH20H
roH
OH OH 22 X = O , Y = S o r X = C H 2 , Y = O o r X = C H 2 , Y = N H
2.1.2.2 Disaccharides. Full 'H and I3C NMR assignments for thirteen glucosylated or galactosylated N-acetylhexosaminitols have been recorded to aid the structural analysis of oligosaccharide alditols related to O-linked protozoan gly~ans.4~ Four 2,3,4-trideuterio-a-~-fucose-containing disaccharides have
327
21: Structural and Quantitative Analytical and Separatory Methods
been synthesized to minimize overlap of ‘H NMR signals and facilitate conformational analysis in saturation transfer difference- (STD-) as well as bioaffinityNMR studies.” NMR spectroscopic investigations have also been undertaken with the following disaccharides: crystalline sucrose moieties;l neocarrabiose and nine of its sulfated and/or pyruvylated derivative^,'^ a series of non-ionizable lactose analogues 22,53cellobiose and five disaccharides containing p-D-glucopyranoside linked to a 6-deoxy- or 2,6-dideoxy-sugar, with the aim of rationalizing the substrate specificities of cardenolide glucohydrolases~4various uridine diphosphoglucose and UDPG.56 Some of the above studies included molecular mechanics and/or molecular dynamics calculations, and the computational studies on the conformational behaviour of C-linked disaccharides and of a number of glycosyl myo- and chiro-inositols referred to above (Refs. 14-16) were supplemented by NMR experiments. 2.1.2.3 Oligosaccharides and Complex Carbohydrates. The lactonization of aN-acetylneuraminyl-(2-.3)-lactose has been studied by NMR and FAB mass spectroscopy.57 A series of per-0-acetylated cellooligomers have been examined by CP/MAS 13CNMR spectroscopy to obtain a structural model for cellulose triacetate in the solid Molecular modelling experiments with trisaccharides 23 and 24 indicated that the (1-,6)-a-linked side chains did not interfere significantly with the stereochemistry of the a-(1-3) backbone of (1+3)-a-~-glucans.~~ a-~-Glcp 1
J.
3 a-~-Glcp-( 1-.6)-a-~-Glcp 23
a-~-Glcp-( 1-*6)-a-~-Glcp-( 1 3)-a-~-Glcp 24 --i,
It has been suggested on the basis of NMR NOE experiments that the conformation of D-gluco-dihydroacarbose bound in the active site of glucoamylase resembles that of the unbound inhibitor in the crystalline state rather than that in solution.60 Conformational effects observed in a NMR ROESY/molecular dynamics simulation study on Man5GlcNAc2and its conjugate with a pentapeptide indicated that the oligosaccharide stabilized the peptide in solution and the peptide influenced the oligosaccharide conformation!’ In addition, the following oligosaccharides and complex carbohydrates have been investigated: the tetrasaccharide 25 and its close analogues 26,62a synthetic octasaccharide fragment of the 0-specific polysaccharide of Shigella dysenteriae type lt3the ganglioside headgroups GM1, GM2, 6’-GM2 and GM4,64 and several analogues of the nucleoside antibiotic adenophostin A.65 Computational solvation studies of cyclodextrins are referred to in Part 1.1.1 above (Ref. 9). 2.1.3 N M R of Nuclei Other Than ‘ H and 13C.A review article containing 19F
328
Carbohydrate Chemistry
a-NeuAc 2
c
3 Hex-(1-.4)-fI-~-Galp-(1~4)-fI-~-GlcpNAc-O( CH2)5NH2 25 Hex = fI-D-GalpNAc 26 Hex = f3-D-GlcpNAcor fI-D-Galp
NMR spectral data of fluorinated carbohydrates (6- and J-data on ca. 130 compounds and including J F , F values of many more) has been published.66A new method for the simultaneous detection of different glycosidase activities in crude culture filtrates involved addition of a mixture of glycosyl fluorides (a-D-ManpF, P-D-ManpF,a-~-GlcpF,P-D-G~C~F, P-D-GalpF, p-CellF, P-D-LacF) to the crude culture filtrates and observation of the changes in the concentrations of individual fluorides by 19FNMR spectro~copy.~~ 2HNMR spectroscopy,in addition to 'H and 13Cmethods, has been used in an analysis of octa-0-decanoylthio-B,B-trehalosein the solid and in the elucidation of the three-dimensional structures of various oligosaccharides containing 2-deoxysugar re~idues.6~ Borate esters of furanoid cis-1,2-diolswere shown by combined llB NMR, 13C NMR and X-ray studies to form bis(dio1ato)borate anions, such as 27.70"B NMR experiments have also been employed to investigate complexes between sugar-based bolaamphiphiles, such as the glucuronamide derivative 28, and the aromatic boronate 29.71 Glycosylmanganese pentacarbonyl complexes have been characterized on the basis of 'H-, I3C-and "Mn-NMR spectral and ten tungstate and seven molybdate complexes of D-gulonic acid in aqueous solutions have been identified by multinuclear NMR studies ('H, I3C,1 7 0 , 9 5 M ~153W).73 ,
IR Spectroscopy. - The FT IR spectra of galactaric acid and its K+,NH4+, Ca2+,Ba2+andLa3+ salts have been recorded and inter~reted.~~ The mid-IR spectra of some trivalent lanthanide complexes of inositols, e.g. PrC13* myoinositol - 9H20, were consistent with their crystal The FT IR spectra for the 2: 1 l-O-a-D-glucopyranosyl-D-mannitol/ethanol adduct supported the X-ray crystallographic results referred to in Part 3.1 Hydrogen bonding in polycrystalline ribitol, xylitol, D-arabinitol, methyl a - ~ manno-, methyl a-D-gluco-and methyl p-D-galacto-pyranosidehas been studied by IR spectroscopy at 20-300 The Raman spectra in the region 20-4000 cm-' of D-glucose and D-fructose in the crystalline state and in the amorphous state with varying water contents, as well as in solution with various sugar concentrations have been recorded. The Raman spectra of the amorphous sugars were found to be very similar to those of their aqueous 2.2
329
21: Structural and Quantitative Analytical and Separatory Methods
27
OH
OH
28
QOOOA
AcO
B
HO' 'OH
/B\
HO
32
OH
OAc
33
H
2.3 Mass Spectrometry. - A review on the use of mass spectrometry for identifying flavonoid glycosides has been published.79 The malonitrile derivatives of oligosaccharides,which were developed for the separation and detection of multi-component oligosaccharidemixtures by negative ion electrospray MS, have now been detected by positive MALDI at considerably lower concentrations,even without prior purification.*' The lactonization of a-N-acetylneuraminyl-(2~3)-lactosehas been studied by FAB MS and NMR specro~copy.~~ The O-isopropylidene and O-benzylidene acetals of several 2,6-anhydro-1-deoxy-1-nitroalditols(P-D-glycopyranosylntromethanes) were studied by EI MS. Distinct differences in the fragmentation patterns of stereoisomers were observed? Negative ion FAB MS gave a simple, abundant and informative fragmentation pattern for ziracin, one of the everninomycin class of oligosaccharide
330
Carbohydrate Chemistry
A method for determining the ee of organic amine salts, such as l-naphthylethylamine hydrochloride, by FAB MS relied on the differential complexation of the R- and S-enantiomers with a deuterium-labelled/unlabelledpodand pair comprising the labelled LL-compound 'Ga12deg-d21(30) and its unlabelled ~~-counterpart.8~ For investigating the site-specific glycosylation in glycoproteins, a strategy based on peptide mass fingerprinting using MALDI-TOF MS, following sequential digestion by a protease and a glycan-specific endoglycosidase, has been de~eloped.'~ 2.4 Other Spectroscopic Methods. - A review (62 refs.) on the elucidation of structures of both natural and unnatural oligomers and polymers, and in particular N-acetylneuraminic acid-containing oligo- and poly-saccharides focussed on the use of circular di~hroism.'~ Improvements in the calculational version of the MOLROT model for describing the optical rotation of simple saccharides have been illustrated by the excellent agreement between observed and calculated values. For example, 309 and 307 deg cm-' dmol-', respectively, were the figures for the optical rotation of methyl a-D-glucopyranoside.86The influence of alkali chlorides and related chlorides (LiCl, NaCl, KCl, CsCl, NH4Cl and Me4NCl) on the rate of the benzoic acid-catalysed mutarotation of N-(pchloropheny1)-P-D-glucopyranosylaminein methanol has been in~estigated.'~ The formation of cyclic esters of boronic acid derivative 31 with monosaccharide diols in aqueous solution causes a large visible colour change from purple to red suitable for use in a diagnostic test paper for glucose in body fluids." The binding events of (sa1en)-Co(I1) complexes with monosaccharides can be monitored by CD-spectral changes (see Tetrahedron, 1999, 55, 9455), and the prochiral (sa1en)-Co(I1)complex 32,bearing two boronic acid groups, has now been proposed for use in sugar 'chirality' sensing at visible ~avelengths.8~ The use of sugar borate complexes for UV-detection in HPLC is referred to in Part 3.1.2 below. An ESR-spectrometric study showed that the anomeric radical formed on treatment of acetobromomaltose with Bu3SnH at ambient temperature undergoes (2-.l)-acetyl migration at elevated temperatures, giving rise to a second radical species 33.90
3
Other Analytical Methods
3.1 X-Ray Crystallography. - No listing of published crystallographic analyses has been prepared this year. Readers are referred to electronic searching methods. The crystal structures of four mannose-derivatives which might exist as either open-chain Schiffs bases or as glycosylamines showed that the hydroxylamine derivative is the oxime 34, whereas the semicarbazide, aniline- and p-chloroaniline-derivatives are the P-glycosylamines 35?l X-Ray diffraction has been used to determine the molecular and crystal structure of 1-0-(a-D-galactopyranosy1)-myo-inositol dihydrate,92and to con-
21 :Structural and Quantitative Analytical and Separatory Methods
33 1
HYNoH
HO
HoQ
HO&
CH20H 34
HR
OH 35 R = NHCONH2, Ph or pCI-C6H4
firm that 1-0-a-D-glucopyranosyl-D-mannitol crystallizes from ethanol as a 2: 1 substrate solvent adduct, the structure being held together by a complex system X-Ray analysis, in addition to DSC and thermogravimetric of hydrogen measurements, has been employed in a study of the thermotropic properties of crystalline long-chain-alkyl a-D-glucopyranosides and their h~drates.9~ 3.2 Physical Measurements. - The use of aryl boronic acid derivatives as sugar sensors is referred to in Part 2.4 above. Partial solubility parameters for mannitol, sucrose and lactose in a wide variety of solvents have been extracted from solubility measurements by use of a modified, extended Hansen method. The solubilities were determined by use of evaporative light scattering detection HPLC?4 The viscosities of glucose, glucitol and maltitol have been measured over eleven orders of magnitude by using capillary tube-, falling spheres-, as well as penetro-vis~orneters?~ The adiabatic compressibilities, apparent molar compressibilities and solvation numbers of fructose and maltose have been calculated from measurements of their ultrasonic velocities in water and in 0.5 M N b C l solution at various temperatures? In addition to X-ray analysis, DSC and thermogravimetric measurements have been used in a study of the thermotropic properties of crystalline long-chainalkyl a-D-glucopyranosides and their hydrates.93 The gelation abilities of four configurational diol sugar isomers, namely methyl 4,6-O-benzylidene-a-~-gluco-, allo- altro- and ido-pyranoside, in several organic solvents have been tested in an attempt to find rules for predicting the gelation abilities of hydrogen bond-based gelat0rs.9~
4
Separatory Methods
A review article on dehydroascorbic acid (72 refs.) covered, in addition to its chemistry, many methods for its separation and analysis?* 4.1 Chromatography. - Reviews of chromatographic methods (HPLC, GLC, capillary electrophoresis) for the quantitative determination of aminoglycoside antibiotic^^^ and of sugars, amino acids and carboxylic acids in foods (175 refs.)'00 have been published. 4.1 .I
Gas-Liquid Chromatography. Selectively substituted y-cyclodextrins, e.g.
332
Carbohydrate Chemistry
the octakis-(2-O-methyl-6-O-Tbdms)-derivative, have been introduced as stationary phases in capillary GC."' GLC determination of reducing end sugar residues in oligo- and poly-saccharides following reduction, hydrolysis and acetylation has been recommended as an alternative to colorimetric and 'H NMR methods."* The iridoid glycosides catalpol and aucubin have been quantified by use of a fast micellar electrokinetic capillary chromatographic method.lo3 4.1.2 High-pressure Liquid Chromatography. A simple and highly sensitive ionexchange HPLC method with UV-detection for measuring small quantities (400pmol) of monosaccharides (Ara, Xyl, Glc, Gal, Man, Fuc, Rha) from pectic polysaccharides has been reported. The sugars were converted to their borate complexes and visualized by addition of ethanolamine to the mobile phase which gave intense absorption at 310 nm.lO4 Reverse-phase HPLC analysis of the enantiomers of the p-adrenergic blocker atendol has been achieved after coupling via the hydroxyl group of the chiral centre with tetra-0-acetyl-P-Dglucopyranosyl isothiocyanate.lo5 HPLC quantification of 2'-deoxyuridine in deproteinated human plasma has been used to follow the effect of administering drugs which inhibit thymidylate synthase.'06 HPLC has also been applied to the quantitative determination of ascorbic acid in food, using monosodium glutam am ate"^ or disodium guanosine5'-rnonopho~phate'~~ in the mobile phase, of sugar alcohols (xylitol, D-glucitol, D-mannitol, maltitol) in confectioneries, after p-nitroben~ylation,'~~ and of carbohydrates in drinks, using a modified amino column and evaporative light scattering detection.'" An HPLC method for determining the partial solubility parameters for mannitol, sucrose and lactose in a variety of solvents is referred to above (Ref. 94). 4.1.3 CoEumn Chromatography. Alditols and free sugars have been determined by high pH anion-exchange chromatography with pulsed amperometric detection."' Analysis of lectin-oligosaccharide interactions by frontal affinity chromatography has been improved by incorporating contemporary LC techniques.' l 2 Brain neuro-chemicals, including ascorbic acid, have been monitored continuously in vivo by microdialysis coupled with LC.'13 LC has also been used to determine ascorbic acid and dehydroascorbic acid in fruit and vegetables '14 and inositol in infant formula and clinical product^."^
4.2 Electrophoresis. - A review on the use of chiral glycosidic surfactants for the separation of enantiomers by capillary electrophoresis has been published.'I6 A considerable increase in the reliability of identifyingcompounds by capillary electrophoresis has been achieved by a reduction in the standard deviation of migration times of various compounds.,including tetramethylrhodamine-labelled oligosaccharides, from ~ 3 %to ( Me Me 148
H
')-Me
0
eM: ? MeO,
Me
glucopyranose by periodate cleavage followed by acid hydrolysis, was converted as indicated into the two bicycles 153 and 154, with the former predominating (ca. 41). In both of these products, the cyano-group occupies an axial position, trans- to the nitrogen lone pair. These were converted into the deoxynojirimycin analogues 155 and 156 by reduction-hydrogen~lysis.~' When 5-bromo-5-deoxyD-xylose (157)was treated with 3-amino-l-propanol, the bicyclic compounds 158 and 159 were obtained. The isomer 158 was produced about twenty times faster, but 159 was the more stable isomer. It was determined that N-alkylations of diastereomeric tetrahydro-1,3-oxazines were the rate-determining steps, and the selective formation of 158 was ascribed to the operation of an anomeric effect that favours the transition state for axial a l k y l a t i ~ n . ~ ~ Ph, i,ii
P
C
m~ +oNCQ m.o Ph,
__t
HO
OH
HO'
'OH
I
I
OH 152
OH 153
OH 154
iii
iii
1
H
HO
bH.2HCI
1
H
'OH
155 156 Reagents: i, (R)-PhCH(NH2)CH20H,KCN; ii, ZnBr2; iii, H2, Pd/C, then EtOH, HCI Scheme 30
Some simpler analogues of the bacterial tyrosyl tRNA synthetase inhibitor SB-219383 have been prepared. Reaction of the nitrone 160, prepared from L-arabinose by intramolecular alkylation of an oxime, with the anion of Ph2C=NCH2C02Etgave the separable isomers of 161. These were converted to 162 and its diastereoisomer, and compounds with opposite chirality in the piperidine ring were made from D-arabinose. Compound 162 had much greater bioactivity than the other three isomers, also displaying selectivity for the
354
Carbohydrate Chemistry
bacterial enzyme over the mammalian one, and it thus seems likely that SB219383 has the stereostructure shown in 163.57 CH2Br
0 U
H H L-Tyr-N &C02H
b 4 M e
O - kI M e 160
NcCPh2 H
Me
161
N-Pmb BnO 164
OH 162
Me
HO
0-
163
4 N
CH~OH 165
CH~OH 166
A number of papers have dealt with sugar-based syntheses of hydroxylated pyrrolizidine alkaloids. The glycosylamine formed from tri-0-benzyl-D-arabinofuranose and p-methoxy-benzylamine was treated with but-3-enylmagnesium bromide, followed by oxidative degradation using PCC to give the lactam 164. This was convertible in a further nine steps to 7-deoxyalexine (165, sugar carbons numbered).'' The same starting material was subsequently used by the same group in a somewhat similar appoach to (+)-alexine (166) itself.59 Tri-0-benzyl-L-xylofuranose was used to make the azido-alkene 167 (Scheme 3 l), which was then converted (ozonolysis, Wittig reaction and oxidation with mCPBA) into the azido-epoxide 168 as a 2:l mixture of two isomers. On ring closure and deprotection as indicated, both ( +)-australhe (169) and (-)-7-epialexine (170) were obtained.60A further synthesis of (+)-australhe has also been reported, proceeding from isopropylidene-D-glyceraldehydevia anhydropentitol intermediates, and using olefin metathesis to establish an eight-membered nitrogen-containing ring, followed by transannular ring closure to the pyrrolizidine.61 A chemoenzymatic route to 7-epi-alexine (170) (Scheme 32) involves the formation of aldehyde 171 from non-sugar precursors, and its coupling with dihydroxyacetone phosphate using fructose 1,6-diphosphate aldolase to give, after acid phosphatase treatment, the ketose 172. This was converted to 7-epialexine (170) as indicated, and related methods were also used to prepare ( +)-australhe (169) and 3-epi-australine (173).62 Reaction of ethyl 2-nitrosoacrylate, produced in situ, with alkene 174 gave the cycloadduct 175 (Scheme 33). Reduction of this with cyanoborohydride, followed by epimerization to the more favoured isomer 176, was followed by Raney nickel reduction of the N - 0 bond and subsequent condensations and reductions to give the pyrrolizidine 177.63
355
22: Carbohydrates in Chiral Organic Synthesis CH20Bn
-
CH20Bn
BnO -
BnO
+ HO
HO
,
\ CH20H OBn OBn OTs 167 168 169 Reagents: i, H2, Pd/C (5 wt.%), EtOH; ii, K2CO3; iii, H2, Pd/C (300 wt.o/,), EtOH Scheme 31 I
HO0
-NHCHO
-
HO
-
Ho
H
H
O
?H a
,
H OH CH20H 171 172 170 Reagents: i, Dihydroxyacetone phosphate, fructose 1,6-diphosphate aldolase; ii, acid phosphatase; iii, 03;iv, H2, Pd/C; v, HCI Scheme 32
CH20H 170
How CH20H 3 N
173
An account of a lecture by Jager incorporates some new work in this area, including the synthesis of the cycloadduct 178 by cycloaddition of a glucosederived nitrone with ethyl acrylate (sugar numbers indicated), and its subsequent conversion to the pyrrolizidine 179.64 A review has discussed synthetic methods for the synthesis of the indolizidine swainsonine and its analogues, covering sugar-based methods as well as other appr0aches.6~When the azido-nitrile 180, prepared from L-sorbose with an inversion of configuration at C-4 (Vol. 33, p. 396), was treated firstly with aqueous TFA and then with Pd-C in methanol, the indolizidinone 181 was obt ained.66
OH
0
x
0
Me Me 174
175
0,
CH20H 176
177
Reagents: i, BrCH2C(NOH)C02Et,Na2C03; ii, NaBH3CN,AcOH; iii, Et3N, CHCI3; iv, Ra Ni, H2, H3B03,MeOH; v, LiBH., Scheme 33 Me--
HO’
0 181
In a route to polyhydroxylated quinolizidines, condensation between the silyl enol ether 182 and aldehyde 183 (Scheme 34) gave the aldol product 184 with high diatereoselectivity.Conditions were also found to obtain diastereoselective condensations between the enantiomer of 183 and either 182 or its precursor ketone to give stereoisomers of 184. Both 182 and 183 were obtained from furan.
356
Carbohydrate Chemistry
Subsequent manipulation (including reduction of the ketone, selenoxide elimination, hydroxylation, Baeyer-Villiger oxidation, and a ring contraction of the product) gave 185, which gave the quinolizidine 186 on reduction and hydrolysis. Two stereoisomers of 186 were made similarly from stereoisomers of 184.67 Four novel isomeric cyclic thiosulfinates, the zeylanoxides, have been isolated from the tropical weed Sphenoclea zeylanica. The structures and absolute stereochemistry of these compounds, which are plant growth inhibitors, have been determined by synthesis from the enantiomers of glucose. Use of L-glucose as outlined in Scheme 35 gave a mixture, separable by HPLC, of zeylanoxide A (187, a-sulfoxide), epi-zeylanoxide A (187, P-sulfoxide), zeylanoxide B (188, asulfoxide), and epi-zeylanoxide B (188, P-sulfoxide), with optical rotations in good agreement with those of the natural products:*
182
'o'.' H
183
184
~~
0
186
Scheme 34
11
185"
187 188 Reagents: i, paraldehyde; ii, NaI04; iii, LiBH4; iv, TsCl, py; v, KSCN; vi, KOH; vii, HCI, H20-MeOH; viii, H202 Scheme 35
6
Acyclic Compounds
An improved method has been described for the conversion of D-arabinose into the aldehyde 189 (sugar carbons indicated), which was then used in a synthesis of a biotinylated 5-HETE for use in affinity ~hromatography.6~ A full account has been given of the conversion of L-erythulose derivatives 190 into their di-cyclohexylboron enolates and reaction of these with aldehydes to give products of type 191, of 2,4-syn-, 4,5-syn-stereochemistry (Vol. 33, p. 10). These compounds can be used, by treatment with periodic acid followed by diazomethane, to make mono-protected dihydroxyesters 192.70 The vinyl epoxide 193 can be made from N-benzoyh-glucosamine in six steps and 38% overall yield (Synth. Commun., 1997, 27,4255), and this has now been used for the synthesis of the sphingadienine-type glucocerebrosides 194.
357
22: Carbohydrates in Chiral Organic Synthesis
Methods were developed to make the 8,g-alkenestereoselectively with either cisor trans-geometry, prior to glucosylation using tetra-0-benzoyl-a-Dglucopyranosyl bromide and AgOTf.71 There has been a further report (see Vol. 28, p. 8 for earlier) on the preparation of conjugated dienes of trans-configuration by treatment of sugar-derived ally1 stannanes with ZnC12.Thus, for example, stannane 195 gave diene-aldehyde 196, and 197 gave 198.72 The C-5 to C-13 fragment 199 of the cytotoxic marine natural product myriaporone 4 has been synthesized from D-glucose, with C-5 to C-8 of myriaporone 4, and the one-carbon branch at C-8, being derived from C-6 to C-2 of the sugar, and a C-9 aldehyde being coupled with an iodoalkene corresponding to C-10 to C-13?3
189
190
Me
192
191
Ph 8
.
D
-
H O H 193
195
"N G l
OH c \ - p OH
196
197
-
O
M (CH2hMe 9
194
"'
OMe
199
7
Carbohydrates as Chiral Auxiliaries and Catalysts
7.1 Carbohydrate-derived Auxiliaries.- Reaction of the fructose-derived acrylate 200 with cyclopentadiene in the presence of Et2A1Cl, followed by disconnection of the auxiliary by reduction, gave the cycloadduct 201 in high ee. Use of the same auxiliary in an intramolecular Diels-Alder reaction catalysed by Et2AlClgave, after reductive disconnection with LiAlH4,the bicycle 202.74It has
358
Carbohydrate Chemistry
previously been shown that 203 can be produced with high endo-selectivity and 90% de by reaction of cyclopentadiene and the isomannide-derived acrylate, catalysed by EtAlCl2(Vol. 30, p. 390-1). It has now been found that higher diastereoselectivitiescan be obtained if the benzyl group is converted into an q6 arene chromium carbonyl complex prior to cycloaddition, and a de of 99% was obtained using the Cr(C0)2[P(OEt)2]complex, again with EtA1C12as Lewis acid catalyst.75
CH20H 201
H 202
203
High levels of diastereoselectivity can be achieved in conjugate radical additions of the type shown in Scheme 36, particularly when the group R' is bulky, and where the protecting group R is an acyloxy or bulky silyl group. In the case where R = Piv and R' = Pri, the product was obtained in 84% yield, and with a de of 86%.76 Two new glucose-derived oxazolidinones have been prepared, and converted to N-acyl derivatives of type 204 (R = Me or Piv). The dialkylboron enolates derived from 204 underwent aldol reactions to give syn-products 205, with diastereomeric ratios between 8:l and 16:1.77The same group has also made the oxazolidinone 206 from D-xylose. When this was treated with Mukaiyama's reagent (2-chloro-1-methylpyridinium iodide) in the presence of an imine, a Staudinger ketene-imine cyclization occurred to give a p-lactam such as 207, the structure of which was confirmed by X-ray crystallography, in >98% de.78 In a synthesis of a potent selective inhibitor of Factor Xa, modified Ugi four-component condensation between tetra-0-pivaloyl-P-Dglucopyranosylamine, pyridine-4-carboxaldehyde, formic acid, and ethyl isocyanoacetate gave the product 208 in high yield and with 81% de. This was subsequently converted to the desired peptidomimetic 209.79 A neat approach (Scheme 37) to the spiroketal 213, a component of the pheromone of the olive fruit fly, involves a base-catalysed oxy-Michael addition between ketosugar 210 and 211 to give stereoselectively the adduct 212, convertible as indicated to the target8' Further examples of hetero-Diels-Alder reactions of carbohydrate-derived chloronitroso compounds have been reported. When the chloronitroso compound 214, made from D-xylose, reacted with cycloheptadiene in the presence of some water, the cycloadduct 215, which could be used in a synthesis of (-)physoperuvine, was obtained in 296% ee, together with the sugar ketone which can be recycled to 214. The pseudoenantiomeric species 216, from L-sorbose, gave the dihydrooxazine 217 on reaction with cyclohexadiene,again in high e.e." The chloronitroso compound 218, easily accessible from D-ribose, underwent
22: Carbohydrates in Chiral Organic Synthesis 0
i
M e Q O % RO
-Me OR
OMe Reagents: i, R'I, Bu3SnH, Et3B/02, Et2AICI,CH2C12 Scheme 36
204
a;* OR
205
'O
359
OMe
p
OMe
CH20Me
@A7 'A 206
H
b02H
0
0
Ph
207
HNYNH2 f N 1
208
OPiv
ii, iii
HO-
(CH2)4*H iv
+
0
212
HO
Reagents: i,CI6Hl3NMe3OH;
HO 213
ii, HS(CH2)3SH,BF3.Et20; iii, HCI, THF iv, Hg(C104)2 Scheme 37
rapid cycloaddition with cyclohexadieneto give the enantiomer of 217 with 96% ee, and reacted more slowly with acyclic dienes to give, for example from sorbic acid, the adduct 219 with >99% ee, after derivatization.82 When the sulfinates 220 (R = Me, Et) were treated with the anions of racemic
360
Carbohydrate Chemistry
3-methylisoxazolines, the products 221 were obtained as a -1:l mixture of separable diastereoisomers. The enantiomers of 221 could be obtained by the use of the isomers of 220 epimeric at In continuation of work in Just's laboratory on the diastereoselectivesynthesis of dinucleoside phosphorothioates (see Vol. 30, p. 290-1, Vol. 32, p. 287), the chlorophosphoramidite 222 (for the synthesis of the aminoalcohol from D-xylose see Chapter 14) was converted as indicated in Scheme 38 into the &-isomer 223, in a 6:l ratio with the diastereomer, and this ratio could be improved by the use of a more hindered base in step ii.84 A study has been reported on the photochemistry of tropolone alkyl ethers within a-,p, and y-cyclodextrins. Moderate asymmetric induction in the bicyclic products 224 were observed in some cases.85
TbdmsO
OTbdms 216
215
Me
214
217
@l:e
Me Me
Y
i, ii
__t
CH~CN
I
PiNH
be
SP
OH 222 223 Reagents: i, 5'-OTbdms-thymidine, Et3N; ii, 3'-OTbdms-thymidine, 2-bromo-4,5-dicyanoimidazole;
iii, Beaucage's reagent; iv, NH3 aq., then TBAF
Scheme 38
Some uses of sugars in novel resolutions of enantiomers have been reported. The ferrocene derivative 225 could be isolated from reaction of a mixture of d,land meso-isomers of the corresponding ferrocene dicarbonyl chloride with This could then be converted methyl 4,6-O-benzylidene-a-~-glucopyranoside. by methanolysis into the enantiomerically-pure (R,R)-ferrocene derivative 226.86 When the chiral pyridinium salt 227 was photolysed, equimolar amounts of the diastereomers 228 and 229 were obtained. Although no chirality transfer occurred, the two isomers could be separated after acetylation, and some further chemistry was performed on the fused aziridine ring of one of the dia-
361
22: Carbohydrates in Chiral Organic Synthesis
stereoi~omers.~~ The acetal 230 was formed by reaction of phthaldehyde with monoisopropylidene-a-D-xylofuranose.On creating a new chiral centre in the form of 231, the two isomers could be separated, and these isomers on methanolysis gave the methyl acetals 232 and the isomers at the asterisked carbon.88
224
225
0
+N CII a-D-dlc-p 227
Ph . ..
226 -OH
I
a-D-dlc-p 228
N
H
I
a-D-dlc-p 229
OBn OMe
CH20Bn 231
232
7.2 Carbohydratesas Chiral Catalysts. - A review on asymmetric epoxidation using chiral ketones as catalysts includes a section discussing the work of, in particular, Shi on the generation in situ of dioxiranes from sugar ketones and oxone, and their use in the asymmetric epoxidation of trans-alkene~.~~ The new mannitol-based diphosphinite ligands 233 (R = Ph, cyclopentyl, cyclohexyl) have been prepared, and used in rhodium complexes for the asymmetric hydrogenation of prochiral ketones. The cases where R = cyclohexyl gave highest enantioselectivity,up to 86% for the reduction of methyl pyruvate to give methyl R-lactate?O A review on carbohydrate complexes of the platinum-group metals includes discussion of the use of such complexes in asymmetric homogeneous hydrogenation of alkenes?’ In this area, the new bisphosphine 234 (‘xylophos’) has been made from D-xylose, and converted to the complex [Rh(cod)(xylophos)] BF4-, which was used for homogeneous hydrogenation of acrylates. For the case of methyl 2-acetamidoacrylate and a-acetamidocinnamic acid, the N-acetylaminoacids were produced in high yields with -90% ee in favour of the Senantiomers?2 The bidentate ligands 235 and 236 have also been made, from D-glucose, and used similarly. The reduction of methyl 2-acetamidoacrylate using the Rh(1) catalyst containing D-glum-ligand 236 occurred with 100% +
362
Carbohydrate Chemistry
conversion to give the S-product with an improved 98% ee.93The bis-phosphite 237, and two related species with similar diphenols, have also been used, as Rh(1) and Ir(1) cationic complexes, in asymmetric hydrogenation, but enantioselectivity in the reduction of acrylates was only moderate. Better enantioselectivity was observed when these complexes were used for the hydroformylation of styrene, with the Rh(1) complex containing 237 giving 238 of 55% ee, with the R-isomer predominant. Use of the D-xylo-analogue of 237 as ligand led to selective formation of the S-enantiomer of 238 (51% ee).94Synthesis of the D-ghco-bisphosphite 239 led to much improved enantioselectivity in hydroformylation [using Rh(acac)(C0)2 and 2391 of styrene and p-substituted styrenes, with styrene itself giving (S)-238 with 90% ee.95 Ligands of type 240 (X = 0,S) have been prepared from D-mannitol and used to catalyse the addition of dialkylzinc reagents to benzaldehyde and heptanal.
BU'
CHO
237
238
0
239
ofMe Me
The ligand 240 (X = 0,R = n-octyl) gave the best enantioselectivity (-goo/,) for the addition of diethylzinc to both aldehydes, with the (R)-enantiomer predominant?6The aminoalcohol241, previously used to catalyse the addition of diethylzinc to aldehydes (Vol. 30, p. 125) has now been used in the addition of diisopropylzinc to a range of aldehydes, giving in each case predominantly the products 242 of addition to the re face of the aldehyde, in all except one case investigated with >90% ee.97Copper-catalysed conjugate addition of diethylzinc to cyclohexenone has been investigated in the presence of the ligand 243, to give under the best conditions found 3-ethylcyclohexanone with ee 62%, favouring the (S)-enantiomer?8The bis-phosphite 244 was investigated more successfully for the same transformation, giving 3-ethylcyclohexanone of (R)-chirality in up to 81% ee?9 D-Glucosamine has been converted into q3-allyl species 245, containing an amphiphilic chiral ligand, which permitted allylic substitutions to occur enantioselectively in aqueous media, or in aqueous-organic biphasic systems. Thus,
363
22: Carbohydrates in Chiral Organic Synthesis
for example, the racemic allylic acetate 246 could be converted into 247 in 95% yield and with 92% ee.Ioo P
O CH~OAC
& : 240
241
@ - k O > AcO
Me
OAc
Me 242
Me
243
o+Me
Me
A sugar-based catalyst for catalytic asymmetric cyanosilylation has been developed. This catalyst, 248, is derived from tri-O-acetyl-D-glucal via the intermediates shown in Scheme 39. It incorporates a Lewis acidic and a Lewis basic site within the molecule, and it was found that the conformational constraint induced by the phenyl group was necessary for good enantioselectivity. Treatment of benzaldehyde and TmsCN with catalytic quantities of 248 gave after acid hydrolysis the cyanohydrin 249 in 80% ee, and several other aldehydes behaved similarly.lo1
E)-
Ph
OMorn
Mom0
Reagents: i , NaBH,,
Morn0
6; Ph
ii-v
OMom
:
vi, vii*
0 A1'
, c,
Ph
249
248 MeOH; ii, MsCI, py; iii, Ph2PK, THF; iv, H202; v, Me2AICI; vi, TrnsCN, PhCHO; vii, Ht Scheme 39
364
Carbohydrate Chemistry
References 1. 2.
3. 4. 5. 6. 7.
8. 9.
10. 11. 12. 13. 14. 15. 16. 17. 18.
19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.
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22: Carbohydrates in Chiral Organic Synthesis
3 6. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.
48. 49. 50. 51.
52. 53.
54. 55. 56. 57. 58. 59. 60. 61. 62. 63.
64. 65. 66. 67. 68. 69. 70.
365
M.S. Chorghade, K. Sadalapure, S. Adhikari, S.V.S. Lalitha, A.M.S. Murugaiah, P.R. Krishna, B.S. Reddy and M.K. Gurjar, Carbohydr. Lett., 2000,3,405. R. Bruns, J. Kopf and P. Koll, Chem. Eur. J., 2000,6,1337. S . Yamauchi and Y. Kinoshita, Biosci. Biotechnol Biochem., 2000,64, 1563. S . Yamauchi and Y. Kinoshita, Biosci. Biotechnol. Biochem., 2000,64,2320. B.B. Snyder and N.A. Hawryluk, Org. Lett., 2000,2,635. M. Sasaki, T. Koike, R. Sakai and K. Tachibana, Tetrahedron Lett., 2000,41,3923. V.N. Desai, N.N. Saha and D.D. Dhavale, J . Chem. Soc., Perkin Trans. I , 2000,147. M.V. Gil, E. Roman and J.A. Serrano, Tetrahedron Lett., 2000,41,3221. K.H. Dotz and E. Gomes da Silva, Tetrahedron, 2000,56,8291. M.M. Faul and B.E. Huff, Chem. Rev., 2000,100,2407. D.S. Tan and S.L. Schreiber, Tetrahedron Lett., 2000,41,9509. G. Matsuo, H. Matsukura, N. Hori and T. Nakata, Tetrahedron Lett., 2000, 41, 7673. H. Matsukura, N. Hori, G. Matsuo and T. Nakata, Tetrahedron Lett., 2000, 41, 7681. H. Fuwa, M. Sasaki and K. Tachibana, Tetrahedron Lett., 2000,41,8371. K. Tomooka, M. Kikuchi, K. Igawa, M. Suzuki, P.-H. Keong and T. Nakai, Angew. Chem. Int. Ed. Engl., 2000,39,4502. A. Pal, A. Bhattacharjya and R. Mukhopadhyay, Tetrahedron Lett., 2000, 41, 10135. K. Tatsuta, M. Takahashi, N. Tanaka and K. Chikauchi, J . Antibiotics, 2000,53, 1231. R. Lysek, B. Furman, Z. Kaluza, J. Frelek, K. Suwinska, Z. Urbanczyk-Lipkowska and M. Chmielowski, Tetrahedron: Asymm., 2000,11,3131. A.K. Bose, B.K. Banik, C. Mathur, D.R. Wagle and M.S. Manhas, Tetrahedron, 2000,56,5603. E. Poupon, B.-X. Luong, A. Chiaroni, N. Kunesch and H.-P. Husson, J . Org. Chem., 2000,65,7208. D.A.Berges, J. Fan, S. Devinck and K. Mower, J . Org. Chem., 2000,65,889. J.M. Berge, R.C.B. Copley, D.S. Eggleston, D.W. Hamprecht, R.L. Jarvest, L.M. Mensah, P.J. O’Hanlon and A.J. Pope, Bioorg. Med. Chem. Lett., 2000,10,1811. H. Yoda, F. Asai and K. Takabe, Synlett, 2000,1001. H. Yoda, H. Katoh and K. Tanabe, Tetrahedron Lett., 2000,41,7661. W.H. Pearson and J.V. Hines, J . Org. Chem., 2000,65,5785. J.D. White and P. Hrnciar, J . Org. Chem., 2000,65,9129. A. Romero and C.-H. Wong, J . Org. Chem., 2000,65,8264. J.K. Gallos, V.C. Sarli, T.V. Koftis and E. Coutouli-Argyropoulou, Tetrahedron Lett., 2000,41,4819. L. Fisera, V. Ondrus, J. Kuban, P. Micuch, I. Blanarikova and V. Jager, J . Heterocycl. Chem., 2000,37,551. A.E. Nemr, Tetrahedron, 2000,56,8579. I. Izquierdo, M.T. Plaza, R. Robles and A.J. Mota, Eur. J . Org. Chem., 2000,2071. C. Schaller and P. Vogel, Helu. Chim. Acta, 2000,83, 193. N. Hirai, S. Sakashita, T. Sano, T. Inoue, H. Ohigashi, C. Premasthira, Y. Asakawa, J. Harada and Y. Fujii, Phytochemistry, 2000,55, 131. S.P. Knanapure, G. Saha, W.S. Powell and J. Rokach, Tetrahedron Lett., 2000,41, 5807. M. Carda, J. Murga, E. Falomir, F. Gonzalez and J.A. Marco, Tetrahedron, 2000, 56, 677.
366
Carbohydrate Chemistry
71. T. Murakami, T. Shimizu and K. Taguchi, Tetrahedron, 2000,56,533. 72. S. Jarosz, S. Skora and K. Szewczyk, Tetrahedron: Asymm., 2000,11, 1997. 73. B.-Z. Zheng, M. Yamauchi, H. Dei and 0.Yonemitsu, Chem. Pharm. Bull., 2000,48, 1761. 74. E.J. Enholm and S. Jiang, J . Org. Chem., 2000,65,4756. 75. G.B. Jones and M. Guzel, Tetrahedron Lett., 2000,41,4695. 76. R. Munakata, K. Totani, K. Takao and K. Tadano, Synlett, 2000,979. 77. M. Stover, A. Liitzen and P. Koll, Tetrahedron: Asymm., 2000,11,371. 78. R. Saul, J. Kopf and P. Koll, Tetrahedron: Asymm., 2000,11,423. 79. S.Y. Tamura, O.E. Levy, T.H. Uong, J.E. Reiner, E.A. Goldman, J.Z. Ho, C.R. Cohen, P.W. Bergum, R.F. Nutt, T.K. Brunck and J.E. Semple, Bioorg. Med. Chem. Lett., 2000,10, 745. 80. H. Watanabe, D. Itoh and T. Kitahara, Synthesis, 2000,1925. 81. A. Hall, P.D. Bailey, D.C. Rees, G.M. Rosair and R.H. Wightman, J . Chem. Soc., Perkin Trans. 1,2000, 329. 82. A. Defoin, M. Joubert, J.-M. Heuchel, C. Strehler and J. Streith, Synthesis, 2000, 1719. 83. J.A. Lopez-Sastre, J.D. Martin-Ramos, J.F. Rodriguez-Amo, M. Santos-Garcia and M.A. Sanz-Tejedor, Tetrahedron: Asymm., 2000,11,4791. 84. Y. Lu and G. Just, Tetrahedron Lett., 2000,41,9223. 85. S. Koodanjeri, A. Joy and V. Ramamurthy, Tetrahedron, 2000,56,7003. 86. S. Shirakami and T. Itoh, Tetrahedron: Asymm., 2000,11,2823. 87. F. Glarner, B. Acar, I. Etter, T. Damiano, E.A. Acar, G. Bernardinelli and U. Burger, Tetrahedron, 2000,56,431 1. 88. D.F. Ewing, C. Len, G. Mackenzie, G. Ronco and P. Villa, Tetrahedron: Asymm., 2000,11,4995. 89. M. Frohn and Y. Shi, Synthesis, 2000,1979. 90. S. Naili, I. Suisse, A. Mortreux, F. Agbossou, M.A. Ali and A. Karim, Tetrahedron Lett., 2000,41,2867. 91. D. Steinborn and H. Junicke, Chem. Rev., 2000,100,4283. 92. 0.Pimies, G. Net, A. Ruiz and C. Claver, Eur. J . Inorg. Chem., 2000,2011. 93. M. Dieguez, 0. Pamies, A. Ruiz, S. Castillon and C. Claver, Tetrahedron: Asyrnm., 2000,11,4701. 94. 0.Pamies, G. Net, A. Ruiz and C. Claver, Tetrahedron: Asymm., 2000,11, 1097. 95. M. Dikguez, 0.Pamies, A. Ruiz, S. Castillbn and C. Claver, Chem. Commun., 2000, 1607. 96. B.T. Cho, Y.S. Chun and W.K. Yang, Tetrahedron: Asymrn., 2000,11,2149. 97. W.K. Yang and B.T. Cho, Tetrahedron: Asymm., 2000,11,2947. 98. 0. Pamies, G. Net, A. Ruiz, C. Claver and S. Woodward, Tetrahedron: Asymm., 2000,11,871. 99. 0.Pamies, M. Dieguez, G. Net, A. Ruiz and C. Claver, Tetrahedron: Asymm., 2000, 11,4377. 100. T. Hashizume, K. Yonehara, K. Ohe and S. Uemura, J . Org. Chem., 2000,65,5197. 101. M. Kanai, Y. Hamashima and M. Shibasaki, Tetrahedron Lett., 2000,41,2405.
Author Index
I n this index the number in parenthesis is the chapter number of the citation and this is followed by the reference number of the relevant citations within that Chapter.
Abada, P. (8) 22 Abantes, M. (20) 136 Abbas, S. (5) 18; (19) 120,231 Abdel-Megied, A.E.-S. (19) 30 Abdou, I.M. (19) 13, 14 Abe, F. (18) 124 Abe, H. (3) 260,307,308 Abe, Y. (3) 218 Abell, C. (18) 176 Abelt, C.J. (6) 6; (7) 75 Abo, S. (9) 60; (16) 24 Abou-Elkair, R.A.I. (19) 41 Abraham, T.W. (19) 263 Abramson, S. (1) 15; (14) 54 Abrantes, M. (19) 210 Abushanab, E. (19) 34 Acar, B. (22) 87 Acar, E.A. (22) 87 Acar, J. (21) 114 Achiwa, K. (9) 72 Ackermann, L. (18) 122 Acquotti, D. (18) 102 Adachi, H. (9) 19; (10) 37; (16) 7 Adachi, I. (18) 86 Adachi, M. (4) 36 Adamczyk, M. (3) 91 Adamski-Werner, S.L. (9) 54 Adelt, S. (18) 129 Adhikari, S. (22) 36 Adinolfi, M. (3) 135; (5) 20; (7) 9; (14) 23 Adiwidjaja, G. (11) 2,20,36; (19) 88 Adjou, A. (19) 290 Adlington, R.M. (19) 127 Afsahi, M. (4) 171 Agaki, M. (19) 144 Agbossou, F. (22) 90 Agoston, K. (1) 16; (10) 58 Agrihotri, G. (20) 106 Agris, P.F. (19) 217 Ahn, M. (19) 29 Ahn, Y.-H. (18) 116; (21) 80 Aiba, S. (4) 215 Aiden, I.S. (6) 10; (12) 16 Airault, M. (14) 52 Ajisaka, K. (3) 166,194; (20) 37,
42 Akimoto, N. (16) 30 Akita, H. (9) 43 Akiyama, T. (21) 120 Al-Abed, Y. (18) 100; (22) 4 Alais, J. (4) 135; (7) 61; (16) 44 Albeck, A. (18) 23 Albermann, C. (20) 92 Albert, M. (3) 144; (8) 4; (20)40; (21) 67 Alberti, A. (21) 90 Albouz-Abo, S. (20) 117 Alcizar, E. (22) 25 Alderfer, J.L. (4) 66, 139, 140, 163-165;(5) 18 Alessandra, B. (3) 188 Alfoldi, J. (10) 104 Alhambra, C. (10) 66; (18) 90 Ali, M.A. (22) 90 Aligiannis, N. (8) 24 Alkabai, S.S. (3) 228 Alkan, S.S. (4) 118; (11) 35 Allart, B. (19) 276 Allef, P. (10) 10 Allen, J.G. (4) 150 Allen, J.R. (4) 1, 150 Allinger, N.L. (21) 2 Alluis, B. (3) 192 Alonso, E. (14) 13 Alonso, R. (22) 28 Aloui, M. (3) 22,242 Altenbach, H.-J. (2) 27; (18) 72, 129 Althoff, J. (21) 119 Altmann, K.-H. (19) 242 Alvarez, R. (19) 97 Alvarez-Manzaneda, E.J. (19) 26 Alves, R.B. (9) 62 Alves, R.J. (6) 8; (9) 62; (10) 84 Alvi, K.A. (4) 61 Aly, M.R.E. (4) 92 Amboldi, N. (3) 52 Ambroise, Y. (3) 53; (20) 109 Amgyal, S.J. (18) 114 Amici, G. (18) 177 Amsler, C.D. (4) 143
367
An, G. (19) 142 An, H. (1)23; (19) 174 Andersch, J. (10) 14 Andersen, G.B. (21) 72 Andersen, O.M. (7) 36 Andersen, R. (21) 111 Andersen, S.M. (18) 21,53 Anderson, A.A. (19) 306 Anderson, J.C. (2) 32; (14) 32 Ando, H. (4) 170 Ando, S. (3) 103; (4) 70 Andre, C. (20) 26 Andrei, G. (19) 143 Andreu, M.G. (14) 58 Andrews, C.W. (21) 39 Andrews, D.M. (7) 22; (16) 22 Andrews, F.L. (3) 285 Andrews, T. (3) 213 Aneja, R. (18) 131 Aneja, S.G. (18) 131 Angulo, J. (21) 16 Angus, D.I. (3) 226 Anilkumar, G. (3) 44, 105; (4) 83; (9) 7; (10) 57; (18) 141 Anitha, N. (2) 40 Anker, D. (3) 197 Ansari, H.R. (21) 96 Antal, Z. (4) 89 Anthonsen, T. (10) 103 Aoki, M. (19) 295 Aoyama, Y. (3) 174 Arai, I. (16) 18; (21) 57 Ararkawa, H. (10) 7 Arasaki, M. (19) 47 Arata, Y. (21) 112 Arcelli, A. (10)65; (11) 4 Archer, F. (9) 50 Ardouin, P. (9) 63 Arkvalo, M.J. (16) 6; (18) 11 Argade, S. (1) 12 Arisawa, M. (18) 85,92 Armstrong, J.I. (3) 177 Arrate, M. (18) 105 Arribas, C. (18) 76 Arroyo-Gomez, Y. (2) 1 Asai, A. (3) 42 Asai, C. (3) 104
368 Asai, F. (22) 58 Asai, M. (21) 71 Asai, N. (19) 152 Asakawa, Y. (22) 68 Asano, N. (18) 84-86,92 Asano, R. (3) 204; (7) 16 Asenjo Asenjo, R. (11) 11 Asensio, J.L. (1) 26; (3) 132; (21) 14, 15,53 Ashida, N. (19) 82 Ashry, E.4.H.E. (4) 92 Ashton, P.R. (21) 88 Aso, M. (15 ) 4 Asonsia, J.L. (3) 219 Assano, N. (18) 32 Aszodi, J. (9) 52; (19) 154 Ataie, M. (5) 31 Atassi, G. (8) 24 Atsumi, M. (4) 203 Attia, A.M.E. (3) 228; (19) 14 Aubertin, A.-M. (3) 93; (7) 64; (19) 51,52,70, 185 Aucagne, V. (3) 272 Audrain, H. (2) 6; (16) 43 Auge, C. (20) 61 AugC, J. (10) 85 Aurrecoechea, J.M. (18) 105 Auxiliadora, M. (10) 84 Auzzas, L. (18) 102 Avalos, M. (16) 6; (18) 11 Averett, D. (3) 328; (19) 11 Awad, L.F. (10) 88; (19) 24 Awano, T. (3) 139 Ayers, J.D. (4) 101 Azema, L. (9) 16 Azhayev, A. (19) 57 Azhayeva, E. (19) 57 Azucena, E. (18) 164; (19) 252 Azuma, S.(19) 77
Balachari, D. (3) 296 Balakumar, A. (5) 14;(19) 254 Balasubramanian, K.K. (13) 4, 13 Baldwin, J.E. (19) 127 Balenkova, E.S.(3) 8 Ballesteros, A. (20) 67 Ballmer, P. (19) 251 Baltina, L.A. (3) 116 Balzarini, J. (2) 20; (3) 335,336; (7) 70; (9) 5; (16) 50; (19) 83, 97,98,101,121 Bamhaoud, T. (1) 18; (4) 100, 133 Banaszek, A. (3) 51; (9) 75 Bandaru, R. (3) 328 Banerjee, A. (19) 164 Banfi, L. (20) 9 Banik, B.K. (22) 54 Banteli, R. (4) 117 Baraldi, P.G. (19) 40 Baran, E.J. (17) 23 Baran, P.S. (9) 25; (13) 6 Baraniak, J. (19) 184 Barascut, J.-L. (19) 124; (21) 36 Baraznenok, I.L. (3) 8 Barbero, J.J. (4) 90 Barchi, J.J., Jr. (19) 34 Bard, J. (19) 11, 16 Baret, N. (19) 108 Barili, P.L. (9) 37; (18) 119 Barillari, J. (3) 227 Barker, W.D. (14) 18; (22) 18 Barlow, J.N. (20) 99 Barni, E. (10) 19 Barolo, C. (10) 19 Barone, G. (3) 135; (7) 9; (14) 23 Barra, J. (21) 94 Barrero, A.F. (19) 26 Barrett, A.G.M. (3) 88 Barriault, L. (3) 126 Baasov, T. (16) 14; (20) 108; (21) Barroca, N. (3) 185 27 Barron, D. (7) 39 Barros, M.T. (7) 19,20 Babiano, R. (18) 11 Bartner, P.L. (21) 82 Babiaro, R. (16) 6 Bartolomi, C. (7) 58 Babu, B.S. (13) 4,13 Baschang, G. (4) 118; (11) 35 Bach, P. (18) 79 Bastrom, M. (20) 98 Bacher, A. (19) 212; (20) 95 Basu, S.(4) 78 Bachki, A. (14) 16 Batley, M. (10)86 Baeschlin,D.K. (4) 122,173; Batsanor, A.S. (18) 157 (18) 137 Bai, Y.(1) 12; (3) 289 Batta, G. (3) 186;(19) 74; (21) 63 Bailey, D. (21) 61 Battistini, C. (3) 52 Battistini, L. (18) 102 Bailey, P.D. (22) 81 Baudoin, 0.(1)17; (4) 2,5; (12) Baiquelet, S. (20) 130 8 Baisch, G. (20) 62 Bauml, E. (3) 195;(21) 50 Baizman, E.R. (3) 48 Bayet, C. (7) 39 Bajza, I. (3) 186, 187 Bazin, H. (21) 15 Baker, D.D. (4) 61 Bazzanini. R. (19) 40 Baker, T.J. (4) 115; (9) 66,67; (18) 169; (19) 168 Beall, J.C.'(3) 88 '
Carbohydrate Chemistry Beaton, M.W. (18) 172 Beau, J.-M. (3) 306,319; (9) 17 Beaudegnies,R. (3) 278 Beaudion, A.R. (19) 198 Beaupkre, D. (2) 22; (7) 66,68; (15) 2; (18) 6,42 Becalski, A. (3) 213 Becker, B. (3) 247; (9) 31; (10) 68; (18) 35 Bedjeguelal, K. (13) 10 Bednarczyk, D. (3) 47; (10) 18 Behr, J.-B. (9) 77 Behrman, E.C. (21) 56 Behrman, E.J. (19) 176; (21) 56 Behrmann, T.L. (3) 303 Behrondt, M.E. (3) 23 Beifuss, U. (16) 52 Beigelman, L. (19) 246 Bekiroglu, S. (21) 31 Belakhov, V. (16) 14; (20) 108 Bell, D.J. (9) 2 Belogi, G. (4) 46 Bilot, F. (4) 62,132; (7) 71 BeMiller, J.N. (3) 254; (18) 28 Benazza, M. (7) 68; (18) 42 Bendas, G. (4) 109 Bender, D.M. (19) 71 Benedetti, Y. (14) 50,52 Bengsston, M. (20) 98 Benito, J.M. (9) 64,65; (10) 46 Benner, K. (21) 70 Bennet, S. (4) 153; (16) 28 Bennett, A.J. (10) 20,21; (20) 113 Bennett, C.E. (4) 151 Bennett, S.M. (22) 3 Benzaria, S. (19) 51,52; (22) 26 Bera, S. (14) 59; (19) 274 Berge, J.M. (22) 57 Berger, E.G. (3) 311 Berger, S.(21) 22 Berges, C. (14) 17 Berges, D.A. (22) 56 Berggren, M.M. (18) 143,144 Bergum, P.W. (22) 79 Beric, 0.(3) 321 Berkin, A. (8) 12; (12) 13 Berkowitz, D.B. (17) 4; (20) 124 Bernabe, M. (7) 58; (20) 67 Bernard, J.B. (9) 54 Bernardi, A. (4) 85; (21) 64 Bernardinelli, G. (22) 87 Bernardini, R. (3) 231 Bernet, B. (19) 285; (21) 28,29 Bernlind, C. (4) 153 Berteina, S. (5) 32; (9) 3; (11) 28 Berthault, P. (4) 171 Berti, G. (9) 37 Bertini, S. (21) 90 Bertolini, R. (3) 50; (19) 267 Bertozzi. C.R. f3) 102.177 \
I
369
Author Index Bessodes, M. (5) 24; (13) 14 Betancor, C. (2) 37; (3) 299 Beuthien-Baumann, B. (8) 6 Beyer, J. (3) 283; (14) 31 Beyreuther, K. (3) 58 BCzay, N. (4) 191 Bhakta, S. (3) 177 Bhat, B. (14) 43; (19) 243 Bhat, US. (3) 229 Bhattacharjya, A. (10) 101; (22) 51
Bhattacharya, S.K.(4) 134 Bhattacharyya, D.K. (22) 26 Bhuiyan, S.H. (2) 15; (20) 127 Bhushan, V. (18) 43,49; (21) 7 Bials, E. (19) 45 Biboutou, R.K. (22) 3 Biegel, T. (3) 177 Bienfait, B. (22) 26,27 Bierer, L. (18) 55 Bilewicz, R. (4) 214 Biovannini, P.P. (3) 339 Biro, C.M. (3) 322 Biron, K.K. (19) 42 Bisagni, E. (19) 70 Biswas, K. (4) 120 Bittman, R. (7) 57 Bizdena, E. (14) 42 Blades, K. (9) 49; (13) 21 Blais, J.C. (3) 77 Blake, C.J. (21) 115 Blanarikova, L. (22) 64 Blanchard, J.S. (20) 99 Blanco, E. (3) 46 Blanco, J.L.J. (21) 62 Blaser, A. (18) 106 Blattner, R. (11) 25 Blayer, S. (16) 15; (20) 87 Blixt, 0. (20) 98 Blonski, C. (9) 16 Bloor, S.J. (7) 35 Blumberg, P.M. (22) 26,27 Blythin, D.J. (19) 136 Bo, Y. (4) 121 Bock, K. (21) 18 Bockovich,N.J. (4) 17 Bodo, B. (3) 130 Bodor, N. (18) 115 Bogusiak, J. (10) 53 Bohner, T.V. (3) 278 Boisch, G. (4) 110 Bolitt, V. (13) 10 Bols, M. (5) 19; (6) 2; (10) 93-95; (18) 38,39,78-80
Bona, M.(19) 283 Bondensgaard, K. (19) 116 Bonetti, G. (21) 115 Bonhours, J.-F. (3) 162 Bonnaffe, D. (16) 44 Bonnefoy,A. (3) 110; (14) 51-53 Booker, B. (14) 37 '
Boons, G.-J. (1) 12;(3) 25, 59,
98, 198; (4) 16,46,159; (21) 21 Borbas, A. (4) 35,89; (5) 17; (6) 3; (21) 24 Borch, R.F. (19) 187,188 Borchardt, R.T. (2) 20; (19) 121 Borgford, T.J. (10) 20 Bornscheuer, U.T. (7) 29; (20) 71 Boronat, A. (14) 4 Boros, S. (11) 6-8 Borovka, N.A. (2) 42 Borowiecka, J. (3) 243 Borrachero, P. (8) 11; (11) 27 Borroni, E. (19) 251 Bortolussi,M. (18) 27 Boryczewski, D. (11) 33; (14) 29 Borysko, K.Z. (19) 44 Boschi, A. (13) 7 Bosco, M.(20) 38 Bose, A.K. (22) 54 Bose, M. (17) 4; (20) 124 Boss, 0.(18) 106 Bosslet, K. (3) 54 Bothe, V. (3) 169 Bouchez, V. (18) 6 Bouchu, A. (3) 217; (6) 5; (16) 39, 40; (20) 82 Boudoin, 0. (14) 10,28 Bouhlal, D. (9) 4 Boulch, R. (3) 30 Boullanger, P. (10) 22 Bouquelet,S. (3) 167 Bourdat, A.-G. (19) 309 Bourgeaux, E. (4) 187 Bousquet, D. (3) 231 Bouyain, S. (4) 87; (7) 62; (18) 46 Bove, H. (4) 63 Bovin, N.V. (3) 200, (4) 8 0 (7) 8; (9) 57 Bowe, C.L. (3) 48 Bowman, K.G. (3) 177 Box, V.G.S.(21) 3 Boyd, V. (19) 103 Boye, H. (16) 46 Boyer, J.L. (19) 179 Boyer, V. (4) 31; (20) 52 B ~ z oE. , (11) 6-9 Brabet, I. (9) 50 Braddock, D.C. (3) 88 Brade, H. (3) 200 Brandi, A. (18) 88 Branstrom, A.A. (3) 48 Brasch, D.J. (4) 60 Bratovanova,E.K. (19) 299 Bredenkamp, M.W. (7) 10; (17) 16,18 Breitenbach, J.M. (19) 44 Brenstrum, T.J. (3) 284,291 Brewers, C.F. (3) 208
Brill, W.K.-D.(5) 32; (9) 3; (11) 28
Brimble, M.A. (3) 284,291; (9) 44
Bringaud, F. (9) 16 Brittain, D.E.A. (10) 63 Brocca, P. (21) 64 Brochette-Lemoine, S. (16) 39 Broddefalk, J. (3) 92 Brooker, S. (18) 158 Brossette, T. (18) 47 Brown, B. (19) 134 Brown, C. (18) 26 Brown, C.A. (19) 94 Brown, C.E.,I11 (19) 48 Brown, D.M. (19) 39 Brown, J.R. (20) 91 Brown, P.N. (4) 136 Brown, R.T. (3) 113 Brunck, J.-S. (11) 2 Brunck, T.K. (22) 79 Brunella, A. (19) 210; (20) 136 Brunet, C. (3) 65; (20) 27 Bruno-Blanch, L. (18) 115 Bruns, C. (4) 117 Bruns, R. (22) 37 Bruns, S. (11) 20 Brust, P. (5) 5 Bryld, T. (19) 109 Brzozowski,D.B. (19) 164 Bubb, W.A. (16) 18; (21) 57 Buchanan, J.G. (5) 31 Buchwald, S.L. (3) 156 Buck, J.R. (19) 33 Bucke, C. (4) 26; (20) 16 Budesinsky, M. (3) 210; (9) 30; (14) 47; (19) 173, 191
Budka, J. (9) 61; (16) 5 Bueno, J.M. (14) 39 Bufo, S.A. (21) 122 Bujacz, G.D. (19) 31 Bundle, D.R. (3) 41; (4) 61; (12) 17
Bunel, S. (17) 22 Bunton, C.A. (17) 22 Burger, U. (22) 87 Burgess, K. (19) 197 Burkhart, F. (3) 257 Burkhart, M.D. (4) 158; (19) 207; (20) 90
Burlina, F. (19) 238 Burmistrov, S.Yu. (7) 49 Burrieza, D. (3) 337 Burton, A. (1) 12 Buskas, T. (3) 85; (4) 55 Busson, R. (19) 179,276,311 Bustamante, P. (21) 94 Butters, T.D. (3) 67; (18) 33 Buttierrez, G. (7) 39 Buzko, P. (19) 10 Byramova, N.E. (3) 200, (9) 57
370 Byun, H.-S. (7) 57
Cataldi, T.R.I.(21) 122 Catelani, G. (6) 7; (9) 37; (18) 119 Cabanillas, A. (16) 6 Cavalanti, S.C.H. (19) 296 Cabrera-Escribano, F. (11) 27 Cerk, V. (10) 65; (11) 4; (18) 123 Cerezo, A.S. (21) 52 Cadet, J. (10) 43; (19) 32 Cai, M . 4 . (3) 170; (4) 95, 130 Cerlutti, M. (20) 61 Cerny, M. (9) 68 Cai, W. (3) 20 Cain, R. (19) 217 Cesar, E.T. (9) 13 Caldeira, M.M. (17) 21; (21) 73 Chahboun, R. (19)26 Caldwell, S.T. (3) 70 Chaicharoenpong, C. (19) 150 Chakraborty, T.K. (9) 14; (18) Calimente, D. (3) 303 Calisto, N. (18) 7 24,25 Callam, C.S. (18) 101 Chakraborty, T.R. (3) 323 Calviello, G. (16) 51 Challiss, R.A.J.(2) 36; (3) 152; Calvo-Asin, J.A. (4) 199 (21) 65 Chamberlain, S.D. (19)42 Calvo-Flores, F.G. (4) 199 Camarasa, M.J. (7) 70; (19) 97, Chambert, S . (19) 76 98 Chambron, S . (19) 209; (20) 94 Caminade, A.-M. (3) 78 Chamorro, C. (7) 70; (19) 97,98 Chan, L. (19) 281 Campa, C. (21) 122 Campbell, A.S. (4) 8; (8) 19 Chan, N.W.C. (20) 63 Camplo, M. (19) 280 Chan, T.H. (18) 89 Campos, N. (14)4 Chan, T.-M. (4) 177; (19) 136 Canac, Y. (3) 271; (10) 109 Chande, M.S. (3) 229 Caiiada, F.J. (1) 26; (3) 132,219; Chandler, A. (2) 35 (9) 20; (21) 14,53 Chandrasekhar, M. (22) 29 Candela, J.I. (3) 46 Chang, A.C.H. (8) 14 Caiiedo-Hernandez, L.M. (19) Chang, C.-W. (9) 9 Chang, G.X. (4) 71 162 Cao, G.-Q. (3) 143 Chang, H.N. (7) 28; (20) 83 Cao, H. (3) 334 Chang, J.Y. (4) 208 Cao, R. (17) 27; (18) 14 Chang, M.-Y. (3) 172; (19) 90 Chang, P.S. (20) 128 Capdevila, J.H. (18) 133, 134 Capozzi, G. (3) 188 Chang, S. (19) 263 Cappellacci, L. (19) 81, 124 Chang, Y.-T. (18) 116 Chaperon, A.R. (4) 173; (18) 137 Caputo, R. (12) 9 Carbek, J.D. (4) 120 Chapleur, Y. (3) 264; (22) 13 Chaplew, Y. (18) 178 Carda, M. (10) 81; (22) 70 Cardona, F. (14) 56; (18) 88,96 Chapman, E. (4) 158 Charon, D. (10) 58 Carell, T. (10) 5 Carlsen, P.J.H. (12) 19 Chary, M.G. (9) 14 Carmelita, M. (20) 96 Chatreaux, F. (14) 52 Carmichael, I. (21) 5 Chatterjee, B.P. (4) 78 Chatterjee, M. (18) 43 Carmona, A.T. (8) 11; (11)27 Carofiglio, T. (4) 212 Chatti, S . (18) 27 Carpintero, M. (3) 274; (18) 149 Chattopadhyaya, J. (19) 4; (21) 38 Carri5, V. (3) 77 Chauchan, K.K. (1) 13 Carrea, G. (20) 67 Chaves, A.L. (18) 170 Carrel, F. (10) 61 Chaves, J.G. (6) 8 Carreno, M.C. (18) 76 Chawla, M. (18) 111 Carrettoni, L. (4) 85 Chen, D.L. (19) 128 Carter, K.N. (19) 307 Chen, G.-R. (2) 33; (10) 16 Carter, N.E. (3) 113 Casiraghi, G. (18) 102; (19) 291 Chen, G.-W. (9) 8 Chen, H. (3) 237 Cassady, J.M. (19) 129 Chen, J.H. (19) 42 Castellino, A.J. (19) 49 Castillon, S. (17) 7,26; (19) 78; Chen, J.J. (19) 19 Chen, K.-C. (10) 16 (22) 25,93-95 Chen, P.Y. (7) 54 Castineiras, A. (17) 27; (18) 14 Chen, S.-H:(21) 113 Castro, M.J.L.(5)22; (7) 18
Carbohydrate Chemistry Chen, S.-T.(3) 83, 172 Chen, X. (18) 175; (20) 100 Chen, X.-M. (3) 64, 132 Chen, Y. (19) 54 Chen, Y.-C. (19) 278 Chen, Y.-H. (6) 11 Chen, Z. (18) 37 Chenault, H.K. (3) 57 Chenevert, R. (22) 23,24 Cheng, F.-C. (21) 113 Cheng, G. (3) 289 Cheng, M.-C. (4) 18; (16) 33; (20) 80 Cheng, Q. (19) 196 Cheng, X. (3) 309; (21) 14 Cheng, Y.-C. (14) 48; (19) 22,59, 107,277,279,296 Cherian, J. (2) 28 Chermann, J.-C.(19) 280 Chernaya, S.S. (2) 42 Chernyak, A. (4) 156 Cherry, P.C. (7) 22; (16) 22 Cheruvallath, Z.S. (19) 224 Chervin, S.M. (8) 22 Chery, F. (6) 4 Cheung, A.W.-H. (19) 72 Chevalier, R. (4) 86 Chhabra, R. (11) 33; (14) 29 Chi, F.-C. (2) 13; (6) 16; (13) 23 Chiang, C.-C. (6) 11 Chiappe, C. (13) 7 Chiara, J.L. (4) 167; (7) 23; (14) 39,40; (18) 138 Chiaroni, A. (18) 71; (22) 55 Chiba, H. (22) 5 Chiba, K. (3) 20 Chiba, M. (3) 297 Chida, N. (10) 3; (22) 9 Chiesa, M.V. (4) 169 Chigorno, V. (20) 125 Chikauchi, K. (22) 52 Chiocconi, A. (3) 34; (12) 12; (20) 116 Chirva, V.Y. (3) 45 Chisholm, J.D. (3) 191; (10) 8 Chiu, M.-H. (3) 207; (14) 19 Chmielewski,M. (5) 27; (10) 102; (21) 34; (22) 53 Chmurski, K. (4) 214 Cho, B.T. (18) 15; (22) 96,97 Cho, D.H. (7) 67 Cho, H. (18) 24 Choe, S.W.T. (14) 34 Choi, H. (16) 27 Choi, J. (18) 87 Choi, S.-R. (18) 66 Choi, S.U.(18) 40, 171 Choi, Y. (14) 48; (19) 22, 107, 145 Chong, P.Y. (3) 80; (4) 186 Chong, Y . (19) 145,146
371
Author Index Choo, D. (19) 89 Chorghade, M.S. (2) 28; (22) 36 Chou, D.T.H. (10) 20 Choudhury, A.K. (3) 32 Chowdhury, U.S. (3) 178 Choy, A.L. (19) 135 Christ, W.J. (10) 69 Christiansen, L. (4) 31; (20) 52 Chron, L. (14) 4 Chu, C.K. (14) 30,48; (19) 22,
59,96, 103, 107, 145, 146, 279,296 Chu, M. (4) 177 Chun, B.K. (14) 30; (19) 59,96 Chun, K.H. (18) 87 Chun, Y.S. (18) 15; (22) 96 Chung, S.-K. (18) 116 Chworos, A. (19) 170,171 Cicchillo, R.M. (8) 20 Cieslak, D. (19) 17,172 Cimino, G. (14) 1 Cintas, P. (16) 6; (18) 11 Cioletti, A.G. (6) 8 Cipolla, L. (3) 270; (7) 11; (18) 52 Ciponte, A.G. (4) 85 Cirelli, A.F. (5) 22; (7) 18 Cirin-Novta, V. (3) 321 Cisarova, I. (9) 30 Citro, M.L. (1) 14 Ciurea, A. (19) 51, 52 Claridge, T.D.W. (10) 63 Clark, A.M. (7) 34; (21) 46 Clary, L. (3) 93; (7) 64 Classon, B. (16) 8,9 Clausen, H. (4) 191 Claver, C. (11) 30; (17) 7,8,26; (22) 92-95,98,99 Clayton, P.T. (21) 84 Clements, P.R. (9) 48 Clive, D.L.J. (4) 121 Cloran, F. (21) 5 Cohen, S.B. (19) 206; (22) 79 Cole, D.L. (19) 224 Collette, P. (19) 154 Collins, B.E. (1) 13 Colliou, V. (3) 337 Combaud, D. (3) 54 Cometa, M.F. (5) 7 Comin, M.J. (19) 163 Comoli, M. (21) 90 Compain, P. (10) 108 Compernolle, F. (18) 47 Comston, C.A. (20) 58 Comte, G. (7) 39 Conbret, J.-C. (4) 187 Cone, M.C. (19) 156 Conley, S.R. (1) 18; (3) 132; (4) 4; (11) 40; (12) 7 Conrad, W.L. (9) 55 Conradt, H.S. (4) 29; (20) 35
Cook, B.N. (3) 177 Cook, P.D. (1) 23; (14) 43; (19) 174,197,243
Cooperwood, J.S. (19) 103 Copley, R.C.B. (22) 57 Corbell, J.B. (3) 78 Cornia, M. (19) 291 Corradini, R. (4) 210 Correa, V. (3) 151,255; (19) 157, 159
Correia, C.R.D. (18) 74 Corsaro, A. (18) 119 Cosstick, R. (19) 90,304 Cossu, S. (6) 4 Cossy, J. (3) 250; (13) 11 Costa, A.M. (19) 68 Costa, P.R.R. (7) 5 Costachel, C. (3) 149; (4) 47, 145 Costantino, V. (12) 5 Costanzo, M.J. (3) 263 Coteron, J.M. (14) 39,40 Cottaz, S. (4) 31; (20) 52 Cottrell, C.E. (21) 56 Coulombeau, C. (19) 309 Courtin, C.M. (21) 102 Coutourier, G. (14) 22 Cox, J.M. (3) 269 Coxon, B. (21) 63 Cramer, C.J. (21) 51 Cramer, F. (19) 195 Cravotto, G. (4) 195; (21) 101 Creemer, L.C. (3) 115 Critminon, C. (4) 207 Crich, D. (3) 20, 38, 160,238; (5) 2; (7) 45; (19) 50 Crimmins, M.T. (19) 135 Crisp, G.T. (9) 48 Critchley, P. (4) 27; (20) 17 Crnugelj, M. (21) 36 Cros, P. (19) 200 Crous, R. (18) 45 Crout, D.H.G. (4) 27; (20) 17, 41,47
Crozier, A. (3) 70 Cruces, M.A. (20) 67 Cryanski, M.K. (10) 100; (14) 21 Csanadi, J. (3) 321 Csavas, M. (4) 89 Csorvasi, A. (19) 74 Cuenoud, B. (19) 242 Cui, J. (4) 104 Cul, Y.-X. (7) 50 Cullis, P.M. (19) 300 Cumpstey, I. (3) 7,67 Cura, P. (3) 22,242 Czech, J. (3) 54 Czernek, J. (21) 6 Czerwinska, G. (19) 217 Daali, Y. (21) 94
Daasberg, K. (13) 3 Dabkowski, W. (19) 195 Dabrowska, A. (10) 59 DAccorso, N.B. (2) 26; (10) 82, 84,89,90
Dagron, F. (7) 65; (13) 20 Dahl, B.M. (19) 115 Dahlman, 0.(21) 123 Dai, Z. (3) 20 Daier, V.A. (17) 25; (18) 7 Daigngeault, S. (4) 121 Dairi, T. (14) 5-7; (19) 211; (20) 139,140
Dalbiez, J.-P. (4) 207 Daluge, S.M. (19) 137 Dam, T.K. (3) 208 Damiano, T. (22) 87 D’Andrea, F. (6) 7; (9) 37; (18) 119
Dang, H.-S. (6) 15 Dangles, 0.(3) 192 Daniels, J.K. (3) 44; (9) 7; (10) 57 Danilov, L.L. (7) 47 Danishefsky, S.J. (4) 1, 134, 150, 160; (7) 27; (9) 26; (10) 30 Daran, A. (10) 58 DaRe, J.M. (19) 48,49 Darini, E. (19) 40 Das, J. (9) 24; (10) 9; (19) 73 Das, P. (4) 177 Das, P.R. (21) 82 Das, S.K. (1) 24; (3) 208,267, 275; (4) 96; ( 5 ) 10
Daskiewicz, J.B. (7) 39 Dasser, M. (22) 23,24 Datta, A.K. (4) 180; (20) 54 Dauban, P. (9) 34,50; (14) 25 Dausse, B. (4) 171 Davey, R.M. (9) 44 David, S. (17) 17 Davies, G.J. (4) 31; (20) 52 Davies, K.M. (1) 14 Davis, B.G. (3) 140, 155; (4) 6; (11) 17
Davis, F.A. (8) 16 Davis, M.G. (19) 42 Davis, T.M. (3) 258; (13) 9 Dawson, M.J. (16) 15; (20) 87 Dax, K. (3) 144; (8) 4; (20) 40; (21) 67
De Almeida, M.V. (9) 13; (17) 29
de Aranjo, T.L. (3) 222; (20) 31 de Armas, P. (3) 325; (18) 63 Debenham, S.D. (3) 268; (4) 51 De Capua, A. (19) 236 de Castro Antunes Felicio, E. (17) 29
Dechanstreiter, M.A. (3) 257 Dechaux, E. (4) 87; (7) 62; (18) 46; (19) 70
372 de Cienfuegas, L.A. (19) 62 De Clercq, E. (2) 20; (3) 335, 336; (7) 70; (9) 5; (16) 50; (19) 6,83,97,98, 101, 121, 143,149 Dkout, J.-L. (19) 76 Deelder, A.M. (20) 43 Deepak, D. (3) 153; (21) 69 Defaye, J. (4) 118; (11) 35 Deffieux, D. (21) 23 de Filho, J.D. (6) 8 Defoin, A. (9)47; (10) 70; (18) 77; (22) 82 Defrancq, E. (19) 200,309 Degn, P. (20) 70 de Groot, A. (3) 29; (20) 115 Dei, H. (22) 73 De Jeso, B. (21) 23 de Kort, M. (2) 36; (3) 151, 152; (9) 11; (19) 160; (21) 65 de la Fuente Blanco, J.A. (19) 162 del Alamo, E.M. (19) 282,283 Delannoy, P. (20) 61 Delbederi, Z. (19) 51,52 Delcour, J.A. (21) 102 de Lederkremer, R.M. (3) 34; (12) 12; (20) 116 Della Bruna, G.S. (19) 280 DellaGreca, M. (3) 216 Delle Monache, F. (5) 7 De Lucchi, D. (6)4 Demailly, G. (7) 68; (18) 10,42 Demange, R. (3) 305,311 De Marino, S. (4) 143 Demassey, J. (14) 52 Demchenko, A.V. (3) 198; (4) 16; (21) 21 de Mesmaeker, A. (5) 32; (9) 3; (11) 28 Demir, N. (21) 114 Demontis, F. (19) 40 De Napoli, L. (19) 236 de Opazo, E. (18) 103, 180; (22) 15,16 de Paz Banez, M.V. (16) 11 Depezay, J.-C. (18) 16, 30,44 Derirt, J. (18) 99 de Roode, B.M. (3) 29; (20) 115 De Rubertis, A. (13) 7 Desai, V.N. (22)42 de Saint-Fuscien, C. (9) 34, 50; (14) 25 Descotes, G. (3) 217; (6) 5; (16) 39,40; (20) 82 Deshmukh, S.P. (10) 44 DeShong, P. (21) 72 Deslongchamps, P. (3) 197 Desvaux, H. (4) 171 Dettmann, R. (4) 105 Deutsch, J.C. (21) 98
Carbohydrate Chemistry Devel, L. (10) 75 Devinck, S. (22) 56 Dhananjaya, N. (16) 13 Dhavale, D.D. (16) 47; (22) 33, 42 Diakur, J.M. (3) 21; (4) 152; (8) 17 Diaz, M.D. (21) 22 Diaz-Aribas, J.C. (9) 20 Diaz-Lanza, A.M. (7) 58 Diaz-Perez, V.M. (9) 20,21; (10) 45 Di Bussolo, V. (9) 27; (13) 5 Dickner, T. (18) 34 Diederich, F. (3) 249; (4) 34; (19) 25 1 Diederichsen, U. (3) 322 Ditguez, M. (17) 7,8,26; (22) 93,95,99 Diele, S. (21) 93 Dietrich, 0.(21) 84 Di Fabio, G. (19) 236 Dilda, P. (19) 101 Dillon, J.L. (1) 11 Di Nardo, C. (16) 16 Ding, G.-J. (3) 290 Ding, J. (3) 203 Ding, M.-Y. (21) 110 Ding, Q.-B. (19) 2; (20) 86 Ding, Y. (4) 110, 118; (11)35; (18) 166 Dini, C. (9) 52; (19) 154 Dinya, Z. (19) 74 Dion, M. (20) 26 DiStefano, C. (10) 83 Distler, J. (20) 92 Dittmann, H. (4) 196 Diwan, P.V. (3) 323; (9) 14 Djedaihi-Pilard, F. (4) 207 Dmochowsak, B. (10) 18 Dobner, B. (3) 75 Doboszewski, B. (19) 99,237 Docsa, T. (10) 48 Dodd, R.H. (9) 34,50; (14) 25 Doi, H.C. (16) 10 Doi, T. (4) 36 Doisneau, G. (3) 306,3 19 Dokurno, P. (10) 59 Dolker, M. (16) 54 Dolle, V. (19) 70 Dolmazon, R. (3) 197 Domingo, L.R. (10) 81 Dominique, R. (3) 267,275; (5) 10 Dondoni, A. (3) 313,317,339; (4) 149; (10) 15; (17) 2; (18) 95 Dong, H.-Q. (13) 27; (18) 55 Donohoe, T.J. (9) 49; (13) 21 DOrleans-Juste, P. (19) 198 Dornsife, R.E. (19) 42
Dorta, R.L. (2) 37; (3) 299 Dory, Y.L. (3) 197 Dosbaa, I. (18) 77 Dossena, A. (4) 210 Dotz, K.H. (17) 13; (22) 44 Doukov, T. (17) 4; (20) 124 Doutheau, A. (3) 197 Dovichi, N.J. (21) 117 Dowd, M.K. (21) 4,51 Drach, J.C. (19) 9, 19,20,42-44, 58 Driguez, H. (4) 31; (20) 52 Driscoll, J.S.(19) 34 Drochon, N. (9) 52; (19) 154 Drueckhammer, D.G. (19) 7 DSouza, F.W. (4) 101 Du, J. (19) 279 Du, J.F. (19) 16 Du, S. (21) 27 Du, Y. (3) 262; (4) 108, 154, 175 Duarte, I. (3) 277; (19) 262 Duarte, T. (14) 17 Dubber, M. (3) 73,74 Dubertret, C. (5) 24; (18) 12 Dubreuil, D. (3) 162; (19) 290 Duclos, R.I., Jr. (4) 64 Ducry, L. (3) 224 Duda, Z. ( 5 ) 26 Dudkin, V. (3) 160; (7) 45 Dudziak, G. (4) 191 Duff, F.J. (18) 97 Duffels, A. (4) 172, 182; (19) 207; (20) 60,90 Duffin, G.R. (3) 87 Dufner, G. (16) 34; (19) 205 Dukhan, D. (19) 124; (21) 36 Dulcere, J.-P. (19) 108 Dulina, R.G. (3) 49; (6) 14 Dunkel, M. (19) 239 Dupradeau, F.-Y. (9) 17 Dupuis-Hamelin, C. (3) 110; (14) 51-53 Durand, S.C. (19) 164 Durand, T. (22) 1,2 Dureault, A. (18) 44 Durik, M. (9) 36 Dussy, A. (19) 310 Duszenko, M. (4) 105 Dutschmann, G.E. (19) 277,278 Duus, J . 0 . (18) 80; (20) 70; (21) 18 Duval, M. (19) 198 Duvold, T. (18) 4 Dwek, R.A. (18) 33 Dworkin, J.P. (2) 47 Dyason, J.C. (9) 60; (16) 24
Ebana, J. (3) 20 Ebisu, H. (19) 155
373
Author Index Edgar, A.R. (5) 3 1 Edmonds, J.S. (17) 12 Ee, G.C.L. (21) 41 Effenberger, F. (9) 40 Efimtseva, E.V. (19) 182 Eger, K. (16) 54 Eggleston, D.S. (22) 57 Eggleston, G. (2) 46 Egron, D. (22) 1 Eguchi, T. (3) 127; (9) 1; (14) 20; (18) 126; (20) 137
Egusa, K. (3) 26 Ehlers, S. (3) 74 Eimermann, M. (20) 29 Eisenreich, W. (19) 212; (20) 95 Ekhart, C. (18) 53 Elango, V. (21) 72 El Ashry, E.S.H. (10) 88; (19) 24
Elgemeie, G.E.H. (3) 228 El Hajji, H. (3) 192 El Hilali, C.M. (5) 3; (7) 25; (18) 20
Ellames, G.J. (3) 87 Ellinq, L. (7) 44 El Rassi, Z. (21) 116 El Shohly, H.N. (7) 34; (21) 46 El Tom, D. (18) 122 Elvebak, L.E., I1 (5) 4 Elzaghheid, M.I. (19) 301,304 Engels, J.W. (3) 327; (19) 12,67, 79,102
Enholm, E.J. (22) 74 Ennis, S.C. (3) 7, 175; (9) 38 Enomoto, A. (19) 161 Enright, P.M. (15) 1 Enriquez, R.G. (21) 47 Eppacher, S. (19) 285 Erata, T. (4) 42; (20) 22; (21) 58 Erbel, P.J.A. (21) 62 Eriksson, S. (21) 38 Erion, M.D. (19) 48,49 Ernholt, B.V. (10) 93; (18) 39 Ernst, B. (4) 110; (20) 62 Escarpe, P.A. (18) 175 Eschenmoser, A. (7) 51 Esko, J.D. (20) 91 Esler, C. (19) 17 Espinola, C.G. (5) 25 Espinosa, J.F. (1) 26 Espliego Vazquez, F. (19) 162 Esumi, Y. (3) 84 Etcheverry, S.B. (17) 23 Etter, I. (22) 87 Euntha, S. (7) 51 Evans, D.H. (14) 38 Evans, G.B. (18) 64; (19) 132 Evans-Lora, T. (21) 3 Evers, M. (19) 290 Ewing, D.F. (22) 88 Eyrisch, 0.(12) 18; (20) 10
Failli, L. (3) 35; (14) 14 Fairbanks, A.J. (3) 7, 67, 155,
Fessi, H. (10) 25 Fessner, W.-D. (12) 18; (16) 26;
Fairweather, J.K. (20) 20 Fakhrnabavi, H. (4) 37 Falck, J.R. (18) 133,134 Falconer, R.A. (10) 33 Falomir, E. (22) 70 Falshaw, A. (18) 54; (20) 121 Falshaw, R. (7) 35 Faltorusso, E. (12) 5 Falvello, L.R. (14) 16 Fan, E. (10) 26 Fan, G.-T. (3) 302 Fan, J. (19) 164; (22) 56 Fan, W. (3) 68 Fan, Y. (20) 89 Fang, J. (20) 100 Fantini, J. (3) 256 Faraco, A.A.G. (9) 62 Farkas, E. (3) 167,187,194; (20)
Festa, P. (14) 23 Fey, S. (7) 44 Fiandor, J.M. (14) 39,40 Fiebig, H.-H. (9) 32 Fiedler, C. (11) 29 Field, R.A. (3) 22,239,242 Fields, G.B. (3) 97 Figueroa-Perez, S. (3) 89 Filho, J.D.de S. (10) 84 Filippov, D.V. (17) 11 Fiorentino, A. (3) 216 Fischer, B. (19) 198 Fischer, R. (13) 25; (16) 3 Fisera, L. (10) 100; (14) 21; (22)
312
42,130
Faroux-Corlay, B. (3) 93; (7) 64 Farquhar, D. (3) 111 Farrugia, I.V. (5) 2 Fascio, M.L. (2) 26; (10) 82 Fashing, M.A. (6) 6; (7) 75 Fatini, J. (3) 93; (7) 64 Faul, M.M. (22) 45 Faure, A. (19) 238 Fazio, A. (9) 41 Fazio, F. (2) 2 Federici, E. (5) 7 Fehkr, K. (4) 35,89; (21) 24 Fehring, V. (19) 90 Feit, B.-A. (1) 15; (14) 54 Feiters, M.C. (3) 98 Felicio, E.de C.A. (9) 13 Fklix, C.P. (4) 213 Felix, I. (19) 39 Fenet, B. (4) 5 0 (7) 39; (10) 25;
(20) 10
64
Fisicaro, E. (10) 19 Fisichella, S. (18) 119 Flack, K. (3) 88 Fleet, G.W.J. (1) 10; (10) 63,64; (18) 32,84-86,92
Flekhter, O.B. (3) 116 Flessner, T. (10) 107 Flitsch, S.L. (7) 44 Flodell, S. (3) 92 Florea, D. (4) 142 Florent, J.-C. (4) 87; (7) 62; (18) 46
Flores-Mosquera, M. (3) 106;
(4) 167; (7) 23; (18) 138,142; (21) 16 Florio, P. (9) 60; (16) 21,24 Foged, C. (18) 73 Foglietti, M.-J. (18) 77 Foldesi, A. (19) 4; (21) 38 Folkersen, B.M. (18) 73 Fontaine, G. (19) 51, 52 Fontana, A. (14) 1 Fontecave, M. (19) 76 (20) 28 Fontenla, J.A. (3) 56 Feng, X. (21) 40 Fontes, A.P.S. (9) 13 Feng, X.-Z. (18) 159 Formanovski, A.A. (7) 8 Ferguson, J.R. (3) 112 Fornasier, R. (4) 212 Fernandez, C. (3) 56 Fort, S. (4) 3 1; (18) 44; (20) 52 Fernandez-Chimeno, R.I. (19) Fossen, T. (7) 36 162 Fossey, C. (19) 51,52 Fernandez-Cirelli, A. (3) 337 Fouace, S. (18) 60 FernLndez-Mayoralas, A. (3) Foubelo, F. (14) 16 56,274; (14) 39,40; (18) 149 Fourrey, J.-L. (19) 238 Fernandez Puentes, J.L. (19) Fox, D.E. (19) 8 162 Fragoso, A. (17) 27; (18) 14 Ferrari, P. (9) 52 Fralich, T.J. (1) 13 Ferreira, M. (14) 17 France, R.R. (3) 67 Ferreira, V.F. (7) 5 Franchetti, P. (19) 124 Ferreo, M. (20) 126 Francisco, C.G. (5) 34; (10) 17 Ferrero, M. (19) 1 Franck, R.W. (12) 1 Ferrier, R.J. (11) 25 Franck-Neumann, M. (9) 39 Ferrikes, V. (3) 30,31 Franco, S. (19) 282-284 Ferroud, D. (3) 110; (14) 50-52 Frank, M. (8)9; (21) 66
374 Frankowski, R. (3) 230; (10) 73 Frannsen, M.C.R. (3) 29; (20) 115 Franz, A. (21) 8 Franzyk, H. (19) 298 Fraschini, C. (16) 41 Fraser, A S . (19)247,248 Fraser-Reid, B. (3) 44, 85, 105; (4) 8, 83; (8) 19; (9) 7; (10) 57; (18) 141 Frechou, C. (18) 10 Free1 Meyers, C.L. (19) 187, 188 Freeman, G.A. (18) 19; (19) 43, 58,271 Freimund, S. (21) 33 Freire, R. (2) 37; (3) 299 Freitag, D. (21) 122 Frelek, J. (2) 3 0 (22) 53 French, A.D. (21) 4,51 Frey, W. (18) 55 Frick, L.W. (19) 42 Froeyen, M. (19) 143 Frohn, M. (22) 89 Frost, C.G. (1) 13 Fu, S.-L. (7) 7 Fuchss, T. (3) 316; (9) 53; (18) 67 Fuchtner, F. (5) 5 Fuentes, F. (9) 20-22; (10)45 Fuentes, J. (10) 47; (19) 21 Fujii, K. (4) 99 Fujii, S. (20) 34; (21) 92 Fujii, Y. (22) 68 Fujimoto, K. (3) 174; (19) 308 Fujimoto, R. (18) 83,93 Fujishima, T. (22) 8 Fujita, K. (4) 188, 193,203,204; (20)25 Fujita, M. (3) 127; (4) 28; (9) 1; (14) 20; (20) 14 Fujita, T. (22) 9 Fujiwara, M. (3) 218 Fukase, K. (1) 20; (3) 26, 180; (9) 73 Fukui, Y. (18) 132 Fukunaga, K. (4) 124, 125; (7) 63; (16) 31 Fukuoka, M. (19) 151,234 Fukuta, M. (20) 85 Fuller, D.J. (3) 121 Fulston, M. (19) 165 Fulton, D.A. (4) 198 Fulton, D.D. (20) 128 Funabashi, M. (3) 221 Fung, K.-P. (4) 82 Furihata, K. (10) 77 Furman, B. (5) 27; (10) 102; (21) 34; (22) 53 Furman, P.A. (21) 39 Furneaux, R.H. (7) 2; (11) 25; (18) 36,64; (19) 132 Furstner, A. (1) 25; (3) 133; (18).
Carbohydrate Chemistry 122 Furuhata, K. (16) 20 Furuike, T. (4) 215 Furukawa, J. (3) 139 Furukawa, J . 4 (4) 114 Furumai, T. (4) 99 Futagami, S. (3) 292 Fuwa, H. (22) 49 Fylaktakidou, K.C. (1) 17, 18; (3) 132; (4) 2-5; (11) 38-40; (12) 6-8; (14) 10,28
63 Garegg, P.J. (4) 116, 174; (18) 140 Garg, T. (19) 263 Garofalo, L.M. (19) 72 Gasch, C. (9) 22; (10)47; (19) 21 Gasparutto, D. (10) 43; (19) 32 Gateau, C. (9) 39 Gaurat, 0.(3) 261; (17) 3 Gauthier, D.A. (3) 263 Gautier, A. (14) 44; (17) 9 Gautier, G. (17) 9 Gautier-Lefebvre, I. (9) 77 Gabrera-Escribano, F. (8) 11 Gautier-Luneau, I. (19) 76 Gacs-Baitz, E. (19) 226 Gauzy, L. (18) 16 Gaderbauer, W. (18) 51 Gavard, 0.(16) 44 Gadikota, R.R. (2) 16; (5) 30; Gavriliu, D. (19) 51, 52 (13) 22; (22)21,22 Gazivoda, T. (9) 5; (16) 50 Gadras, C. (3) 93; (7) 64 Gege, C. (4) 79, 109, 126 Gago, F. (19) 97 Gelin, M. (3) 31 Gaillard, F. (9) 17 Gen, E. (19) 119 Gainsford, G.J. (18) 64; (19) 132 Gendron, F.-P. (19) 198 Gait, M.J. (19) 250 Georgen, J.-L. (20) 61 Galaverna, G. (4) 210 Georges, A.T. (3) 280 Galbis, J.A. (16) 11 Gkrard, S. (2) 23; (10) 106 Gergely, P. (10) 48 Galceran, M.T. (21) 121 Galeffi, C. (5) 7 Gerken, M. (3) 54 Gallagher, T. (3) 266 Gerling, S. (3) 101; (10) 27 Gallegos, A. (18) 143 Gerull, A. (1) 15; (14) 54 Gervay-Hague, J. (21) 85 Gallos, J.K. (22) 63 Gerz, M. (4) 54; (10) 29 Gama, Y. (10) 40 Gesson, J.-P. (3) 54 Gambert, U. (4) 29; (20) 35 Gamou, G. (3) 212 Geurts, H.P.M. (3) 98 Geyer, A. (4) 79 Gamsey, S. (19) 66 Gan, Z. (3) 225; (16) 35 Ghisalba, 0.(19) 210; (20) 136 Ghosh, A.K. (3) 111; (18) 24 Ganem, B. (3) 256 Ganguly, A.K. (4) 32; (19) 136; Ghosh, M. (3) 49; (6) 14 (21) 82 Ghosh, S. (3) 323; (14) 18; (18) Gani, D. (18) 172 24; (21)48; (22) 18 Gao, C.-W. (3) 207; (14) 19 Gibson, F.S. (1) 11 Gao, K. (19) 12 Gibson, V.C. (3) 88 Gao, M.-Y. (14) 48; (19) 107 Giese, B. (19) 310 Gao, X. (5) 21 Gil, M.V. (22) 43 Gil, V.M.S. (17) 21; (21) 73 Gao, X.-M. (4) 200 Gilbert, M.R. (3) 105; (4) 93; Garcia, B.A. (3) 10 (18) 141; (20) 89 Garcia, J. (19) 309 Gildersleeve, J. (4) 123 Garcia, M. (2) 19; (3) 6; (4) 73; Gill, I. (2) 49, 50; (3) 28; (20) 46 (17) 5; (19) 261 Garcia, S. (4) 148; (18) 139; (21) Gill, M. (3) 128, 129 16 Gillitt, N.D. (17) 22 Garcia-Echeverria, C. (19) 242 Gin, D.Y. (3) 10; (9) 27; (13) 5 Garcia-Fernandez, J.M. (9) 20, Giovannini, P.P. (1 8) 95 21,64,65; (10) 45,46 Girardet, J.-L. (19) 17 Girijavallabhan, V.M. (21) 82 Garcia Gravalos, D. (19) 162 Garcia-Herrero, A. (3) 219; (21) Giuliano, R.M. (3) 35; (9) 29; (14) 14,27 53 Glacon, V. (7) 68; (18) 42 Garcia-Martin, M.G. (16) 11 Garcia-Moreno, M.I. (9) 20,64; Gladkaya, V.A. (19) 53 Glarner, F. (22) 87 (10) 46 Garcia-Ruano, J.L. (18) 76 Glomb, M.A. (15) 6 Garcia-Tellado, F. (3) 325; (18) Glunz, P.W. (4) 160; (7) 27
375
Author Index Gnauck, M. (5) 5 Gnecco, D. (21) 47 Goda, S . (18) 1 Godage, H. (3) 312 Gode, P. (9)4 Godfredsen, C.H. (21) 18 Godsckesen, M. (18) 69 Goethals, G. (9) 4 Goh, K. (9) 42 Gokmen, V. (21) 114 Gola, J. (2) 33 Goldman, E.A. (22) 79 Goldstein, B.M. (19) 124 Goldstein, I.J. (4) 217 Golisade, A. (19) 63 Gomes, J. (21) 67 Ghmez, A.M. (3) 6; (4) 73 Gomez, I. (14) 13 Gomez da Silva, E. (22)44 Gomez-Guillen, M. (8) 11; (11) 27 Gonda, J. (9) 30 Gonzalez, A. (14) 9 Gonzalez, F. (22) 70 Gonzalez, J.C. (18) 7 Gonzalez, Z . (14) 9 Goodman, B. (18) 7 Goodman, M. (4) 115; (9) 66, 67; (18) 169 Goodman, S.I. (3) 257 Goodnow, R.A. (19) 72 Gordon, M.T. (3) 220 Gore, V.K. (3) 301 Gorls, H. (9) 70 Gosselin, G. (12) 14; (19) 46,60, 185 Goti, A. (18) 88 Goto, K. (4) 72; (21) 59 Gotor, V. (19) 1; (20) 126 Gottfredsen, C.H. (3) 51 Gottschaldt, M. (9) 70 Goud, P.M. (2) 16; (5) 30; (13) 22 Gouhier, G. (14) 44 Gould, S.J. (19) 156 Gourlain, T. (2) 22; (7) 66; (15) 2 Gouyette, A. (9) 63 Grabez, S. (22) 20 Grabley, S. (7) 40; (18) 159 Grabowski, J. (3) 133 Grachev, M.K. (7) 49 Graciet, J.-C.G. (19) 3 Gracza, T. (18) 58,59 Gramlich, V. (10) 5 Grandjean, C. (3) 96 Granet, R. (3) 77 Granger, C.E. (4) 213 Gras-masse, H. (3) 96 Grassi, J. (4) 207 Grathwohl, M. (7) 15 Graves, B.J. (18) 175
Gravier-Pelletier, C. (18) 16 Gray, G.R. (5) 3,4; (7) 25; (18) 20 Graziani, A. (3) 189 Gredley, M. (16)28 Green, D.F. (10) 2; (11) 13 Green, L.G. (4) 122, 172, 173, 182; (18) 137; (20) 60 Green, M.P. (3) 140; (11)17 Greenberg, M.M. (19) 306,307 Greenberg, W.A. (18) 162 Greer, S.P. (4) 143 Greffe, L. (4) 31; (20) 52 Greimel, P. (18) 51 Greiner, J. (3) 1,93; (5) 8; (7) 64 Greul, J. (13) 27 Greyling, H.F. (18) 45 Gridley, J.J. (3) 36, 175; (9) 38 Griengl, H. (13) 25; (16) 3 Grierson, D.S. (19) 70 Griesgraber, G.W. (19) 183,263 Griesser, H. (10) 67 Grifantini, M. (19) 124 Griffey, R.H. (18) 166 Griffin, E.J. (2) 32; (14) 32 Grill, S . (19) 22 Groaning, M.D. (18) 110 Grond, S. (7) 40 Gronwald, 0.(6) 18; (21) 97 Gropper, S . (21) 27 Grosdemange-Billiard, C. (14) 2 Gross, P.H. (3) 318 Grosse, C. (12) 18; (20) 10 Grotenbreg, G. (3) 66 Groves, M.J. (5) 2 Groziak, M.P. (19) 122; (21) 37 Grugier, J. (3) 277; (19) 262 Gryaznov, S.M. (19) 65,66 Grynkiewicz, G. (13) 16 Grzeszczyk, B. (2) 18 Gu, J.-H. (11) 12 Guan, H.-P. (19) 294 Guanti, G. (20) 9 Guariniello, L. (3) 135; (5) 20; (7) 9; (14) 23 Guarogna, A. (12) 9 Gudmundsson, K.S. (19) 9,58 Guenot, P. (4) 207 Guenther, R. (19) 217 Guerrini, M. (21) 90 Gueyrard, D. (3) 227,272 Guile, S.D. (19) 134 Guillaumel, J. (19) 70 Guillerm, G. (9) 77 Guillot, J.C. (19) 154 Guilloton, M. (3) 77 Gullen, E. (19) 22,277-279 Gum, A.G. (20) 141 Gumina, G. (19) 22, 103, 145, 146,279 Gunay, N.S. (20) 142
Gunic, E. (19) 16, 17 Gunji, H. (14) 46; (19) 286,288, 289; (22) 14 GUO,C.-T. (3) 55; (16) 29 Guo, F. (19) 275 Guo, M.J. (19) 39 Gupta, A. (3) 282; (14) 55 Gurjar, M.K. (2) 28; (22) 36 Gurskaya, G.V. (19) 28 Gururaja, T.L. (4) 69 Gutman, A.L. (3) 114 Gutteridge, C. (11) 1; (19) 86 Guy, A. (22) 2 Guyot, M. (22) 34 Guzarev, A.P. (19) 214,230 Guzel, M. (22) 75 Gyemant, G. (20) 119 Gyepesova, D. (9) 36 Ha, D.-C. (19) 29 Ha, T.-K. (4) 208 Haase, W.-C. (1) 4; (4) 12, 39 Habib, E.-S.E. (3) 125 Habuchi, 0.(20) 85 Hacht, S. (20) 95 Hacking, D.R. (19) 259 Hada, N. (4) 76,97, 137; (16) 36 Hadad, C.M. (3) 220 Haddad, J. (18) 164; (19) 252 Haddleton, D.M. (19) 261 Hadwiger, P. (8) 13; (10) 62; (13) 1; (20) 134 Haeberli, P. (19) 246 Haesslein, J.-L. (3) 110; (14) 50-52 Haga, L. (3) 165 Hager, C. (6) 17; (10) 55, 56,60 Hagihara, K. (22) 5 Hagino, S . (4) 52 Hahn, M.G. (4)122, 173; (18) 137 Haines, A.H. (2) 29 Hajduch, J. (5) 26 Hakamata, W. ( 5 ) 1; (12) 10; (20) 110 Hakamaya, W. (20) 111 HAkansson, A.E. (19) 113,114 Hakimelahi, G.H. (5) 14; (19) 254 Halada, P. (20) 64, 135 Halbfinger, E. (19) 198 Halcomb, R.L. (19) 206 Halkes, K.M. (3) 51; (4) 81 Hall, A. (22) 81 Hallberg, A. (16) 8,9; (20) 47 Haller, M. (1) 12 Hallis, T.M. (20) 129 Haltrich, D. (20) 135 Ham, W.-H. (18) 75 Hamacher, K. (8) 6
376 Hamamoto, T. (19) 203; (20) 104 Hamana, H. (4) 111; (5) 16; (6) 13 Hamasaki, K. (3) 107; (9) 81 Hamashima, Y. (22) 101 Hamburger, M. (4) 57 Hamernikova, M. (9) 15 Hammache, D. (3) 93,256; (7) 64 Hamprecht, D.W. (22) 57 Hamura, T. (3) 286 Han, K.-C. (22) 26 Han, M. (3) 253,318; (11) 26 Han, M.J. (4) 208 Han, X. (4) 103 Hanachi, I. (3) 95 Hanashima, S. (11)24 Handa, S.S. (3) 294 Hanessian, S. (3) 9, 52; (7) 41; (17) 6 Hanna, I. (22) 17 Hansen, S.U. (10) 95; (18) 78 Hansen, T. (13) 3 Hanson, R.L. (19) 164 Haque, W. (4) 152; (8) 17 Harada, J. (22) 68 Harada, Y. (4) 129 Haraguchi, K. (19) 119 Haramuishi, K. (19) 151 Harata, K. (3) 218 Harden, T.K. (19) 179 Harding, J.R. (3) 112 Harger, M.J.P. (19) 300 Hari, Y. (3) 330,331; (19) 117, 130,131 Harigaya, Y. (19) 161 Harita, N. (3) 146 Haroutounian, S.A. (9) 78 Harpham, B. (19) 240 Harris, C.R. (4) 160; (7) 27 Harris, G.J. (21) 25 Harris, J.M. (2) 4, 5; (16) 2 Harrison, B. (1) 11 Hart, J.B. (20) 121 Hartley, R.C. (3) 70 Hartmann, S. (3) 87 Hartonen, K. (21) 103 Harvey, R.J. (18) 19; (19) 42,271 Hasan, M. (21) 96 Hasegawa, T. (3) 79; (19) 189 Hasegawa, Y. (22) 35 Haselhorst, T. (3) 195; (21) 50 Hashimoto, H. (3) 211; (4) 193; (9) 10; (11)3; (18) 65, 152; (20) 25,56 Hashimoto, I. (4) 48 Hashimoto, M. (20) 78 Hashimoto, S.(4) 65 Hashimoto, Y. (18) 132 Hashizume, T. (22) 100
Carbohydrate Chemistry Haslinger, E. (4) 57 Hassan, A.E.A.(19) 35,41 Hassan, H.H.A.M. (2) 21; (22) 30 Hatakana, K. (20) 96 Hatanaka, C. (21) 104 Hatanaka, Y. (10) 78 Hattori, M. (7) 33 Haubner, R. (3) 257 Hausler, H. (18) 31,51 Havlicek, J. (9) 15 Hawryluk, N.A. (22) 40 Hayakawa, T. (14) 35; (18) 130; (20) 143 Hayakawa, Y. (10) 77 Hayashi, J.-C. (4) 21 1 Hayashi, K. (3) 202; (7) 31; (20) 79 Hayashi, M. (3) 252; (13) 17; (19) 161 Hayashi, N. (3) 281; (18) 124 Hayauchi, Y. (9) 59; (10) 24 Hayes, C.J. (19) 120,231 Hazell, R.G. (2) 6; (10) 93; (16) 43; (18) 39 He, K. (19) 192 He, L. (7) 57; (19) 240 He, P. (4) 48 He, S. (20) 112 He, X. (20) 106 He, Z.4. (3) 293 Hecht, S. (19) 212 Hegde, V.R. (19) 138,139 Heimark, L. (21) 82 Hein, M. (8) 8,9; (21)66 Heinen, A.W. (18) 8 Hellebrandt, W. (3) 195; (21) 50 Hemmerich, S. (3) 177 Hena, M.A. (9)42 Hendrix, C. (19) 143 Hendrix, M. (20) 7 Henin, Y. (19) 290 Henne, P. (7) 40 Hennig, L. (10) 14 Hennings, D.D. (19) 71 Herbert, J.M. (3) 87 Herczegh, P. (4) 35,89; (21) 24 Herdewijn, P. (19) 143, 179,182, 276,3 11 Herfurth, L. (21) 26 Hergold-Brundic, A. (9) 5; (16) 50 Hermann, C. (18) 18 Hermann, T. (9) 79 Hernandez-Matteo, F. (3) 208; (4) 199,216 Herold, P. (4) 117 Herrera, A.J. (5) 34; (10) 17 Herscovici, J. (18) 12 Herve du Penhoat, C. (21) 55 Herz, S. (19) 212; (20) 95
Herzner, H. (4) 13;(10) 28 Hetzer, G. (2) 33 Heuchel, J.-M. (10) 70; (22) 82 Hidano, T. (21) 92 Higson, A.P. (4) 119 Higuchi, R. (4) 127,129 Hildenbrand, K. (19) 305 Hilgers, P. (13) 27 Hill, D.C. (4) 56 Hill, G.C. (21) 8 Hindsgaul, 0.(3) 184; (4) 25,49, 110;(5)6;(12) ll;(16)53; (20) 2, 120 Hines, J.V. (22) 60 Hinzen, B. (4) 122 Hirabayashi, J. (21) 112 Hirai, K. (3) 219; (21) 53 Hirai, N. (22) 68 Hirai, Y. (18) 57 Hirama, M. (3) 134 Hiramoto, Y. (10) 39 Hirao, K. (19) 303 Hirata, Y. (3) 148; (18) 13 Hiroka, S. (14) 60 Hirooka, M. (3) 104; (4) 52,98 Hirschmann, R.(3) 224 Hisamatsu, M. (4) 201 Hisamitsu, H. (19) 126 Hitomi, Y. (2) 10 Ho, J.Z. (22) 79 Hodgson, A. (3) 273; (18) 22 Hoefller, J.-F. (14) 2-4; (18) 2 Hoeoeg, C. (21) 68 Hoffmann, B. (21) 93 Hofs, R. (18) 159 Hofstadler, S.A. (18) 166 Hoh, J.T. (11) 31 Hohan, H. (10) 74 Hohl, R.J. (19) 190 Hojo, H. (3) 103; (4) 14 Hokke, C.H. (20) 43 Hol, W.G.J. (10) 26 Holderich, W.F. (16) 37 Hollingsworth, R.J. (18) 61; (22) 19 Holm, B. (3) 92 Holman, G.D. (5) 9 Holmes, A.J. (16) 48 Holt, D.J. (14) 18; (22) 18 Holy, A. (19) 148 Holzapfel, C.W. (18)45 Holzmann, G. (3) 257 Honda, K. (18) 124 Honda, Y. (20) 78 Hong, H. (19) 96 Hong, J.H. (14) 30,48; (19) 107 Hong, L. (19) 187 Honma, T. (10) 7 Hoogmartens, J. (19) 3 11 Hoornaert, G.J. (18) 47 Hopwood, J.J. (9) 48
377
Author Index Horbowicz, M. (3) 121 Hori, M. (7) 24 Hori, N. (22) 46,48 Horie, K. (4) 111 Horie, Y. (19) 216 Horiguchi, T. (19) 196 Horii, I. (19) 47 Hornberger, M. (21) 54 Horton, D. (8) 14; (10) 91; (17) 28 Horuat, S. (7) 17 Horvath, A. (19) 74 Hosakawa, Y. (3) 39 Hosken, M. (4) 61 Hosoda, A. (18) 117 Hosokawa, T. (3) 61; (20) 33,34 Hosoya, T. (3) 292 Hotokka, M. (21) 78 Hotta, K. (18) 160, 161; (20) 75, 76 Hou, Z. (10) 26 HOU,Z.-J. (4) 200 Houge-Frydrych, C.S.V. (9) 2; (19) 165 Hounsell, E.F. (21) 20,61 Howard, S. (20) 112 Howarth, O.W. (20)47 Howell, J. (19) 164 Hrebabecky, H. (19) 148 Hricoviniova, M. (14) 8 Hricoviniova, Z. (14) 8 Hrnciar, P. (22) 61 Hsieh, Y.-T. (6) 11 Hu, J.-J. (7) 50 Hu, L. (19) 259 Hu, Y. (18) 136, 143, 144 Hu, Y.-J. (5) 10 Hu, Y.-Z. (4) 121 Huang, B.-G. (4) 165 Huang, D.H. (10) 23 Huang, J. (20) 113 Huang, R.-F. (4) 141 Huang, X. (3) 314; (16) 32 Huang, Z. (21) 68 Huang, Z.-T. (3) 64 Hubrecht, I. (18) 150 Hudlicky, T. (18) 120 Huet, F. (19) 105,292 Huff, B.E. (22) 45 Huffian, L.G., Jr. (9) 27; (13) 5 Hufford, C.D. (21)46 Hughes, N.A. (11) 10,15 Hui, Y. (3) 203; (4) 82, 103; (16) 42 Humber, D.C. (7) 22; (16) 22 Hummel, G. (3) 233; (10) 35 Humphrey, A.J. (18) 68; (20) 12 Hung, S.-C. (2) 13, 14; (6) 16; (13) 23 Hungerford, N.L. (10) 64 Hunziker, J. (3) 50; (19) 267
Hursthouse, M.B. (18) 11 HUS,T.-S. (3) 302 Husken, D. (19) 242 Husson, H.-P. (18) 71; (22) 55 Huuskonen, J. (21) 76 Huwig, A. (21) 33 Hwang, J.-T. (19) 306 Hwu, J.R. (5) 14; (19) 254 Hyldtoft, L. (13) 28
Inoue, A. (19) 258; (20) 81 Inoue, H. (7) 42,43 Inoue, K. (13) 17 Inoue, T. (22) 68 Inoue, Y. (2) 43; (3) 119; (4) 200, 209 Iori, R. (3) 227 Iorizzi, M. (4) 143 Ireland, I.D. (21) 117 Iriarte-Capaccio, C.A. (9) 76 Isac-Garcia, J. (4) 199 Iadonisi, A. (3) 135; (5) 20; (7) 9; Ishida, H. (1) 16; (2) 43; (4) 20, 124, 125, 179; (7) 63; (16) 31 (14) 23 Ibarra, C. (17) 22 Ishida, H.K. (3) 199 Ibatullin, F.M. (10) 50,51 Ishiga, K. (19) 203 Ishigami, K. (22) 32 Ibrahim, E.-S.I. (4) 92 Ichiba, N. (3) 136; (7) 78 Ishige, F. (20) 104 Ichikawa, E. (19) 150 Ishihara, J. (22) 5 Ishihara, T. (19) 258; (20) 81 Ichikawa, M. (3) 232; (4) 217 Ichikawa, S. (3) 259,260; (18) 29 Ishii, A. (4) 14 Ichikawa, T. (19) 189 Ishii, T. (19) 258; (20) 81 Ichikawa, Y. (1) 13; (3) 232; (4) Ishikawa, H. (18) 135 Ishikawa, S. (19) 92 15,217; (10) 42 Ishikura, M. (19) 147 Ichimura, K. (18) 3 Ishitsuka, H. (19) 47 Igarashi, Y. (4) 99 Ismida, N. (7) 76 Igawa, K. (22) 50 Iglesias-Guerra, F. (3) 46 Isobe, M. (10) 42; (22) 7 Ignatenko, A.V. (21) 35 Isobe, R. (4) 129 Iha, M. (4) 127 Isonishi, S. (3) 295; (12) 4 IJzerman, A.P. (19) 15 Itabashi, M. (4) 157 Ikami, T. (1) 16; (4) 20 Itakura, M. (3) 103 Ikeda, A. (6) 18 Itami, Y. (2) 15; (20) 127 Ikeda, K. (9) 72; (16) 23; (18) Ito, K. (22) 5 84-86,92 Ito, M. (3) 117 Ikeda, M. (21)97 Ito, Y. (3) 103,214; (4) 14,54, 70,138, 162, 170,183; (10) Ikeda, T. (3)40;(4) 58 Ikeda, Y. (4) 157; (18) 160, 161; 29 (19) 308; (20) 75,76 Itoh, D. (22) 80 Ikefuji, A. (4) 52 Itoh, T. (7) 76; (17) 15; (22) 86 Ikegami, S. (2) 10; (3) 136; (7) 78; Itoh, Y. (19) 119 Itonori, S. (1) 13 (18) 98, 155, 156 Ivanov, A.R. (21) 118 Ikeuchi, Y. (16) 30 Ikuta, A. (4) 192-194; (20) 25 Ivanova, G.D. (19) 299 Ivanova, I.A. (4) 119 Ilangaran, A. (3) 332 Illaszwicz, C. (21) 67 Iwai, Y. (2) 10 Iltis, A. (14) 50, 52 Iwano, Y. (3) 181, 182; (7) 52 Imai, H. (3) 134 Iwasa, A. (4) 52 Imamura, H. (5) 28; (21) 83 Iwase, H. (21) 107, 108 Imanishi, T. (3) 330,331; (19) Iwase, K. (19) 155 Iwata, C. (18) 1 117,130,131 Imbach, J.-L. (12) 14; (19) 60, Iwata, I. (21) 65 Iwata, Y. (2) 36; (3) 152 124, 185; (21) 36 Imberty, A. (1)8; (21) 1 Iwayama, S. (19) 295 Immel, S. (4) 188; (21) 9 Iyer, R.P. (19) 177 Imperiatore, C. (12) 5 Iyer, V.V. (19) 183 Imura, K. (3) 292 Izquierdo, I. (3) 298; (19) 62; Inagaki, J. (3) 154; (4) 43; (7) 46 (20) 69; (22) 66 Inagaki, M. (4) 127 Izquierdo Cubero, I. (11) 11 Inazu, T. (3) 154; (4) 43; (7) 46 Izumi, M. (4) 158 Incarvito, C.D. (14) 38 Izumida, M. (4) 203 Ince. S.J. 14) 122. 173: 118) 137 Izumori, K. (2) 15; (20) 127 I
\
I
I
7 ,
I
378 Jackman, A.L. (21) 106 Jackson, R.J. (20) 63 Jackson, W.R. (16) 10 Jacob-Roetne, R. (19) 251 Jacobs, A. (21) 123 Jacobsen, J.P. (19) 106,116 Jacobsen, K.A. (19) 179 Jacquinet, J.-C. (3) 185, 196; (4) 62, 132; (7) 71 Jacquinod, M. (19) 32 Jaeschke, G. (12) 18; (20) 10 Jager, E.-G. (9) 70 Jager, V. (10) 67; (13) 27; (18) 55; (22) 64 Jagerovic, N. (10) 66 Jain, M.L. (5) 14; (19) 254 Jain, R.K. (4) 140,165 Jakel, C. (17) 13 Jakobsen, A. (10) 93; (18) 39 James, T.D. (21) 88 Janczuk, A. (20) 100 Jang, D.O. (7) 67 Jang, S.-Y. (19) 179 Janicka, M. (4) 56 Janisz, B. (9) 75 Janknecht, H.-H. (10) 105 Jankowska, J. (19) 172,193 Janossy, L. (5) 17; (6) 3 Janssen, C.O. (4) 88 Janssen, G. (19) 311 Jansson, A.H. (3) 51 Jaquinod, M. (10) 43 Jaramillo, C. (3) 274; (18) 149 Jaramillo-Gomez, L.M. (18) 120 Jaroskova, L. (3) 263 Jarosz, S. (2) 17,30 (13) 18,24, 29; (22) 11, 12,72 Jarvest, R.L. (22) 57 Jas, G. (1) 14 Jaslin, G. (5) 24 Jaunzems, J. (1) 14 Jayalakshmi, B. (6) 12 Jayamma, Y. (18) 43,49; (21) 7 Jayaprakash, S. (3) 323; (9) 14 Jayaram, H.N. (19) 124 Jkhan, P. (4) 207 Jenkins, D.J. (3) 150; (19) 158, 159 Jenkins, G.N. (7) 30; (20) 65 Jenkins, J. (4) 177 Jenkins, P.R. (14) 18; (22) 18 Jensen, H.H. (18) 79,80 Jensen, K.B. (10) 93; (18) 39 Jensen, K.J. (9) 69 Jeong, E.N. (18) 87 Jeong, 1.-Y. (18) 40 Jeong, T.-H. (18) 116 Jeric, I. (7) 17 Jesberger, M. (1) 14
Carbohydrate Chemistry JeSelnik, M. (3) 71 Jia, Z. (4) 104 Jiaang, W.-T. (3) 83, 172 Jiang, H. (2) 31 Jiang, S. (18) 157; (22) 74 Jiao, H. (3) 184 Jimenez, J.L. (16) 6; (18) 11 Jimenez-Barbero, J. (1) 26; (3) 132,219; (21) 14, 15,53 Jimeno, M.L. (19) 97 Jin, Y. (19) 177 Jin, Z. (3) 132;(5) 21; (11) 4 0 (12) 7 Joannard, D. (16) 39,40 Jobron, L. (3) 233; (10) 35 Jochims, J.C. (10)92 Joh, T. (18) 130; (20) 143 Johnson, A.W. (21) 84 Johnson, D.A. (12) 2; (20) 107 Johnson, D.V. (13) 25; (16) 3 Johnson, G.P. (21) 5 1 Johnson, M. (1) 12 Johnston, B.D. (3) 235; (4) 107, 136; (10) 2, 12; (11) 12, 13 Johnston, J.N. (3) 126 Joly, G.J. (18) 47,48 Jona, H. (3) 137, 138, 176; (4) 40,41 Jones, B.C.N.M. (19) 304 Jones, C. (21) 49 Jones, G.B. (22) 75 Jones, J.B. (3) 140;(11) 17 Jones, J.L. (19) 165 Jones, P.S. (7) 22; (16) 22 Jong-Jip, P. (10) 78 Jonklass, M.D. (19) 69 Joo, Y.H. (7) 67 Jerrgensen, K.A. (2) 6; (9) 45,46; (10) 11;(16) 43 Jorgensen, M. (13) 1 Joseph, L. (13) 10 Joswig, C. (19) 187 Joubert, M. (9) 47; (10) 70; (22) 82 Joutel, J. (3) 30 Joy, A. (22) 84 Joyce, G.F. (7) 53 Ju, Y. (7) 50 Jung, A. (1) 14 Jung, C.M. (18) 171 Jung, K.-H. (1)5; (3) 4; (4) 7 Jung, K.W. (7) 1 Jung, K.-Y. (19) 190 Jung, M.E. (14) 34; (19) 104, 140,247 Junicke, H. (17) 1; (22) 91 Jurczak, J. (4) 214 Jurisch, C. (3) 265 Just, G. (14) 15,43; (19) 222, 223,243; (22) 84
Kababya, S. (21) 27 Kabir, A.K.M.S. (7) 12 Kaca, W. (3) 47 Kachalova, A.V. (19) 250 Kaczmarek, J. (7) 4 Kaczmarek, R. (19) 184 Kaczynski, Z. (7) 4 Kadokawa, J.-i. (3) 20 Kadokura, M. (19) 180 Kadota, S. (3) 68 Kadun, A.L. (3) 45 Kaffke, W. (20) 94 Kageura, T. (3) 119 Kahlig, H. (11)29 Kahn, A. (19) 261 Kahn, M.L. (17) 27; (18) 14 Kahn, 0.(17) 27; (18) 14 Kahne, D. (4) 120,123 Kai, T. (16) 20 Kainosho, M. (19) 37; (20) 131 Kaji, E. (3) 39, 146 Kajihara, Y. (3) 211; (4) 67; (13) 12; (19) 258; (20) 56,81,97 Kajimoto, T. (4) 58; (20) 6 Kajtar-Peredy, M. (19) 226 Kakarla, R. (3) 49; (6) 14 Kakayan, E.S. (3) 45 Kakehi, A. (3) 252 Kakinuma, K. (3) 127; (9) 1; (14) 20; (18) 126;(20) 137 Kaldapa, C. (3) 77 Kaluza, Z. (5) 27; (10) 102; (21) 34; (22) 53 Kamasaki, K. (18) 163 Kameda, Y. (18) 84-86,92 Kamerling, J.P. (3) 179; (4) 81; (7) 26; (21) 62 Kamiya, T. (3) 199 Kammerer, J. (18) 125 Kan, T. (18) 104 Kan, Y. (4) 99 Kanai, M. (22) 101 Kanai, S. (3) 181, 182 Kanazaki, M. (19) 110; (20) 122 Kandra, L. (20) 119 Kane, R.R. (19) 69 Kaneda, K. (14) 5-7; (19) 211; (20) 139,140 Kaneko, S. (3) 202; (20) 78 Kanemitsu, T. (1)21 Kang, J.-H. (22) 26 Kang, S.H. (16) 27 Kang, S.-J. (16) 1 Kanie, 0. (1)21; (3) 55,66; (16) 29; (18) 50,94 Kanie, Y. (3) 55; (16) 29; (18) 50, 94 Kaplon, P. (3) 237 Kappes-Roth, T. (20) 141 Kapur, M. (18) 56 Karihara, K. (7) 77
379
Author Index Karim, A. (22) 90 Karlsson, T. (21) 40 Karpeisky, A. (19) 246 Karpenko, I.L. (19) 186 Karst, N. (3) 196 Kartha, K.P.R. (3) 22,242 Kary, P.D. (18) 120 Kasai, K.4. (21) 112 Kasper, H. (5) 5 Kasprzykowska, R. (18) 17 Kassab, R. (10) 25 Kassem, T. (19) 185 Kassim, A. (21) 41 Kassou, M. (22) 25 Kasuya, Z. (20) 96 Katagiri, N. (19) 147 Kate, S.D.(16) 49 Katipally, K.R. (18) 133 Katiyar, S. (15) 5 Katkevica, D. (14) 42 Kato, A. (18) 86 Kato, H. (3) 205; (19) 189 Kato, K. (4) 52; (19) 150,244 Kato, N. (3) 120 Kato, Y. (19) 161 Katoh, H. (22) 59 Katopadis, A. (20) 62 Kaukinen, U. (19) 301 Kaustov, L. (21) 27 Kautz, U. (13) 27 Kawabata, H. (3) 252; (13) 17 Kawabata, M. (3) 281 Kawada, T. (3) 204; (7) 16 Kawaguchi, T. (4) 111; (19) 189 Kawai, T. (4) 170 Kawakami, R.P. (18) 31 Kawameto, T. (16) 30 Kawamoto, M. (10) 7 Kawamura, M. (4) 189; (20) 30, 132 Kawana, M. (7) 72; (19) 264 Kawano, S. (4) 42; (20) 22 Kawano, Y. (4) 72; (21) 59 Kawasaki, A.M. (19) 247-249 Kawasaki, H. (19) 175; (20) 133 Kawashima, E. (19) 43 Kazmierski, S. (19) 31 Kaztopodis, A. (4) 110 Kebrle, J. (5) 26 Keefer, L.K. (1) 14 Keeling, S.P. (7) 22; (16) 22 Kefurt, K. (9) 15 Keim, H. (4) 88 Kekomaki, K. (19) 302 Keller, M. (18) 125 Kelley, J.A. (19) 34 Kelly, D.R. (14) 41; (22) 10 Kelly, S. (1) 11 Kelson, I.K. (1) 15; (14) 54 Kelterer, A.-M. (21) 51 Kempin, U. (10)'78
Kenmoku, H. (3) 120 Kenne, L. (4) 144; (21) 30,31 Keong, P.-H. (22) 50 Keranen, M.D. (2) 4 Kern, E.R. (19) 294 Kerremans, L. (19) 276 Kessler, H. (3) 257 Kett, W.C. (10) 86 Kettrup, A. (21) 122 Khan, J. (2) 20; (19) 121 Khan, J.A. (3) 27; (20) 1 Khan, N. (3) 132,309; (21) 14 Khan, S. (3) 111 Khanbabaee, K. (21) 9 Khandazhinskaya, A.L. (19) 186 Khare, A. (3) 153; (21) 69 Khare, N.K. (3) 153 Khatuntseva, E.A. (4) 75 Khau, V.V. (7) 69 Khiar, N. (3) 106; (4) 148; (11) 19; (18) 139, 142; 121) 16,42 Khider, J. (14) 52 Khrebtova, S.B. (21) 35 Kieburg, C . (3) 81; (9) 23 Kiefel, M.J. (3) 226; (16) 28; (20) 117 Kierzek, R. (19) 167 Kiess, F.-M. (10)67 Kiguchi, T. (18) 70 Kihlberg, J. (3) 92,215 Kikuchi, M. (22) 50 Kikuchi, T. (3) 134 Kilonda, A. (18) 47 Kim, B.H. (19) 100 Kim, C.V. (18) 175 Kim, G. (3) 329 Kim, H. (19) 141 Kim, H.J. (7) 14 Kim, H.O. (19) 179 Kim, H.S. (3) 329; (7) 76 Kim, J.S. (16) 27 Kim, J.Y. (19) 100 Kim, K.B. (21) 56 Kim, M. (2) 18 Kim, S.N. (7) 14 Kim, S.R. (7) 37 Kim, S.Y. (18) 171 Kim, W. (19) 141 Kim, Y.C. (7) 37 Kim, Y.-H. (7) 33; (18) 75; (19) 89 Kim, Y.-K. (20) 32 Kim, Y.S. (20) 142 Kimura, K. (4) 200 Kindahl, L. (21) 30 King, B.W. (19) 135 Kinghorn, A.D. (16) 1 Kinjo, J. (4) 58 Kinoshita. Y. (22) 38.39 Kinsman, R.G. (5) 31 ~
I
Kinzy, W. (4) 126 Kirby Mayanard, D. (4) 205; (7) 60 Kirihata, M. (20) 78 Kirk, S.R. (18) 167 Kirkpatrick, P.N. (20) 129 Kirn, A. (19) 51, 52 Kirschning, A. (1) 14; (9) 8 Kirst, H.A. (3) 115 Kirzhner, M. (18) 164; (19) 252 Kishi, Y. (19) 38 Kishigami, M. (16) 30 Kishihara, S. (3) 61; (20) 33, 34; (21) 92 Kisilevsky, R. (8) 12; (12) 13 Kiso, M. (1) 16; (3) 199; (4) 20, 124, 125, 179; (7) 63; (16) 31 Kiso, T. (3) 222,223; (7) 32; (20) 31,39,114 Kissick, T.P. (19) 164 Kitagawa, T. (3) 295 Kitagawa, Y. (3) 164; (20) 57 Kitahara. T. (22) 32.80 Kitahata; S. (3) 222,'223; (4) 193, 194; (7) 32; (20) 24,25, 31,39,114 Kitahawa, T. (12) 4 Kitamoto, D. (21) 48 Kitamura, A. (19) 216 Kitano, K. (19) 82,112 Kitao, S. (20) 132 Kitaoka, M. (3) 202 Kitazume, T. (14) 60 Kittaka, A. (19) 119; (22) 8 Kittaka, H. (18) 98 Kittakoop, P. (3) 122 Kiyonaka, S. (3) 95 Kiyooka, S.-I. (9) 42 Kiyosada, T. (4) 30; (20) 4 Kizu, H. (18) 84-86,92 KlafTke, W. (10) 32; (15) 3; (19) 208,209 Kleban, M. (13) 27 Klegraf, E. (20) 74 Klemm, D. (9) 70 Klich, M. (3) 110; (14) 50-53 Klier, A.H. (10) 84 Klufers, P. (21) 70 Knanapure, S.P. (22) 69 Knapp, S. (3) 301; (10) 38 Knaus, E.E. (3) 335,336 Knerr, L. (4) 155; (7) 15 Kniezo, K. (14) 47 Kniezo, L. (3) 210 Koashi, Y. (10) 3 Kobayashi, A. (4) 14 Kobayashi, E. (19) 258 Kobayashi, F. (20) 81 Kobayashi, H. (18) 57 Kobayashi, K. (3) 79, 164; (4) 74; (20) 57 ,
380 Kobayashi, S. (4) 30,114; (20) 4, Kopf, J. (22) 37,78 74 Koreeda, M. (8) 22 Kobayashi, Y. (18) 168 Kornilov, A.V. (4) 128 Kobe, J. (10) 52, 54 Koroteev, M.P. (21) 35 KoEevar, M. (3) 71 Kosciolowska, S. (2) 17 Kochkar, H. (16) 37 Koshimizu, K. (18) 117 Kodama, E. (19) 112 Koshino, H. (11) 24 Kodama, T. (19) 75 Koshkin, A.A. (19) 113 Koeller, K.M. (1) 6,7; (4) 22, Koslov, I.A. (19) 276 141, 180, 181; (20) 3,54, 59, Kosma, P. (3) 200; (4) 19 88,102 Kostina, V.G. (19) 53 Koert, U. (19) 12, 102 Koszalka, G.W. (19) 9,42,43 Koessler, J.-L. (4) 148; (18) 139 Kotera, M. (19) 309 Koftis, T.V. (22) 63 Koto, S. (3) 104; (4) 52,98 Kotra, L.P. (18) 164; (19) 252 Koga, K. (4) 204 Koga, T. (20) 132 Koulocheri, S.D. (9) 78 Kohchi, Y. (19) 47 KovaE, P. (8) 14 Kohgo, S. (19) 112 Kovacik, V. (21) 81 Kohli, T. (3) 195; (21) 50 Kovacs, I. (19) 101 Koike, T. (22) 41 Kovacs, J. (16) 4 Kovenski, J. (3) 33,337; (5) 22; Koikov, L.N. (3) 253; (11) 26 Koizumi, K. (4) 192-194;(20) (7) 18 24,25 Kover, K.E. (4) 35; (21) 24 Kojima, F. (9) 19; (10) 36; (16) 7 Koyano, T. (4) 157 Kojima, N. (19) 18 Kozerski, L. (21) 34 Kok, S.H.L. (18) 174 Kozikowski, A.P. (18) 136,143, Kolehmainen, E. (17) 19,24; 144 (21) 17 Kragl, U. (7) 44 Ko11, A. (10) 41 Krajcik, J. (10) 100; (14) 21 Koll, P. (3) 209; (16) 4; (22) 37, Krajewski, P. (5) 27; (10) 102 Kralikovi, S. (19) 173,191 77,78 Krallmann-Wenzel, U. (3) 74 Kolodziej, H. (7) 38 Kramer, S. (4) 44; (16) 45 Koman, M. (18) 58,59 Komatsu, Y. (19) 244 Kramyu, J. (3) 122 Kraszewski, A. (19) 172,193 Komiya, M. (3) 104; (4) 52 Kraus, J.-L. (19) 280 Komiyama, M. (19) 303 Krausz, P. (3) 77 Kondo, H. (3) 86 Krayevsky, A.A. (19) 186,233 Kondo, K. (19) 225 Kreis, W. (21) 54 Kondo, M. (19) 119 Kondo, S. (4) 157; (18) 160, 161; Kren, V. (20) 64 Kreszewski, A. (19) 169 (20) 75,76 Kretzschmar, G. (7) 21 Kondratyuk, I.V. (10) 6 Krintel, S.L. (4) 90 Kong, F. (4) 38,91, 102,108, Krishna, P.R.(3) 332,338; (22) 154, 168, 175, 176; (19) 23 Kong, J.Y. (3) 60; (20) 23 36 Krishna, U.M. (18) 133,134 Kong, Y. (3) 320 Konig, S. (21) 119 Krishnamurthy, R.(7) 51 Krishnudu, K. (2) 35; (3) 338 Konig, W.A. (4) 196 Kronenthal, D.R. (19) 164 Konishi, K. (16) 23 Kroutil, J. (9) 68 Konitz, A. (3) 230; (10) 18,59, Kryczka, B. (3) 236; (11) 32 73; (21) 44 Kono, H. (4) 42; (20) 22; (21) 58 Krygowski, T.M. (10) 100; (14) 21 Kononov, L.O. (4) 128 Krzewinski, F. (3) 167; (20) 130 Konradsson, P. (3) 85; (4) 55, Ksebati, M.B. (19) 293,294 116,174; (18) 140 Ktajewski, P. (21) 34 Kontrohr, T. (3) 186 Kuang, D. (21) 41 Koodanjeri, S. (22) 84 Kuang, R.(19) 136 Koomen, G.-J. (19) 15 KOOS,M. (9) 36; (10) 76; (12) 15; Kuban, J. (22) 64 Kuberan, B. (20) 142 (13) 26 Kubo. K. f4) 138 Kopcho, J.J. (19) 48,49
Carbohydrate Chemistry Kuboki, A. (19) 258; (20) 81 Kudelska, W. (3) 251 Kudo, F. (18) 126; (20) 137 Kugiyama, Y. (3) 212 Kugler, R.(13) 27 Kuhla, B. (10) 98; (14) 57 Kulak, T.I. (19) 202 Kulkarni, M.G. (16) 49 Kumabe, N. (3) 103 Kumar, G.M. (13) 15 Kumar, R. (19) 114-116 Kumar, S. (19) 39 Kumazawa, T. (3) 279,288,297 Kumihara, H. (3) 86 Kundu, M.K. (19) 4 Kunert, 0.(4) 57 Kunesch, N. (18) 71; (22) 55 Kung, H.F. (18) 66 Kung, M.-P. (18) 66 Kunimori, M. (19) 181 Kuno, A. (3) 202 Kunwar, A.C. (2) 35; (3) 323, 338; (18) 24
Kunway, A.C. (9) 14 Kunz, H. (3) 234; (4) 13,112,
113, 191; ( 5 ) 11; (10) 10,28, 34 Kunz, 0.(16) 52 Kurakata, S.-I. (3) 181, 182; (7) 52 Kurasawa, 0.(19) 220,221 Kurata, T. (8) 15 Kurihara, M. (22) 8 Kuriyama, Y. (3) 286 Kuroda, K. (4) 137 Kuroi, H. (18) 86 Kurokawa, K. (3) 86 Kurosawa, H. (3) 84 Kurszewska, M. (18) 17 Kuruma, I. (19) 47 Kusamoto, H. (19) 119 Kusano, G. (18) 83,93 Kusumoto, S. (3) 26, 180; (9) 73 Kusunoki, A. (4) 98 Kuszmann, J. (11) 6-9 Kuzuhara, H. (3) 84 Kuzuyama, T. (14) 5-7; (19) 211; (20) 139, 140 Kvaernra, L. (19) 27,115 Kvarnstrom, I. (16) 8,9 Kvasyuk, E. (19) 215 Kwon, H.C. (18) 171 Kwon, Y.-U. (18) 116
Laaksonen, A. (21) 12 Laatikainen, R.(19) 57 Laatsch, H. (9) 32 Laayoun, A. (19) 200 Labrinidis, G. (21) 13 Lachaud. S. (14) 50.52
Author Index La Colla, P. (19) 40 Ladurke, D. (19) 51,52 Lafarga, R. (17) 25 La Ferla, B. (3) 173,270 (4) 53; (18) 52; (20) 72,73 Lafont, D. (10) 22 Lahmann, M. (4) 59 Lakhrissi, M. (3) 264 Lakhrissi, Y. (3) 264 Lakshmi, N.S. (18) 49; (21) 7 Lakshminath, S. (18) 121,151 Lalitha, S.V.S. (22) 36 Lamb, A.J. (2) 29 Lamberth, C. (3) 324 Lamosse, T.A. (5) 3; (7) 25; (18) 20 Lang, J. (21) 6 Lang, M. (3) 101; (10) 27 Langer, H.-J. (7) 40 Langer, V. (9) 36 Langlois, B.R. (4) 213 Lanskaya, I.M. (3) 142; (20) 144 Laranya, B. (3) 332 Large, D.G. (21) 61 Larrazabal, G. (17) 22 Larsen, D.S. (3) 285; (4) 60; (18) 158 Larsen, K. (3) 141 Larsen, K.L. (20) 70 Larsen, L. (3) 285 Lartigue, J.-C. (21) 23 Laschat, S. (18) 34 Laskar, D.D. (9) 18 Lassaigne, P. (3) 110; (14) 51-53 Lattt, K.P. (7) 38 Lattova, E. (21) 81 Lauer-Fields, J.L. (3) 97 Laurin, P. (3) 110; (14) 50-53 Lay, L. (3) 173,270; (4) 53; (7) 48; (20) 72,73 Le, T.X. (21) 72 Le, X. (21) 117 Leblanc, G. (3) 53; (20) 109 Lebreton, J. (19) 290 Leclercq, F. (18) 12 Lecroix, F. (4) 50; (20) 28 Lederer, M.D. (9) 6 Lee, B.W. (18) 40 Lee, C.K. (2) 31 Lee, C.S. (19) 22 Lee, C.-W. (21) 113 Lee, D. (16) 1 Lee, E.E. (4) 107 Lee, I.D. (20) 23 Lee, J. (3) 94; (10) 31; (22) 26 Lee, J.D.(3) 60 Lee, J.K. (18) 171 Lee, J.Y. (7) 14 Lee, K. (3) 320; (16) 1 Lee, K.R. (18) 171 Lee, K.-Y. (18) 75
38 1 Lee, M. (19) 300 Lee, N. (19) 281 Lee, S.-H. (16) 1 Lee, T.H. (3) 60; (20) 23 Lee, Y.C. (20) 96 Lee, Y.S. (7) 14 Leeflang, B.R. (21) 62 Leenders, R.G.G. (7) 6 Lefeber, D.J. (7) 26 Leforestier, J. (21) 55 Legoy, M.-D. (3) 65; (20) 27 Legrand, P. (21) 43 Legraverend, M. (19) 70 Lei, Z.-H. (12) 3; (19) 273 Lelong, B. (19) 51,52 Lemanski, G. (3) 5, 158, 159; (4) 37,94 Le Merrer, Y. (18) 16,30 Lemoine, G. (19) 154 Lemoine, R. (4) 135; (7) 61 Lemoine, S. (16) 40 Len, C. (22) 88 LeNarvor, C. (3) 240; (20) 55 Le Nouen, D. (18) 77 Lenz, R. (4) 182; (20) 60 Leonce, S. (8) 24 Lergenmiiller, M. (4) 183 Leroy, E. (18) 106 Lescop, C. (19) 105,292 Lesnik, E.A. (19) 248,249 Lessen, T.A. (21) 72 Levine, M.J. (4) 69 Levitt, M.H. (21) 40 Levsen, K. (4) 166 Levy, O.E. (22) 79 Lew, W. (18) 175 Lewin, N.E. (22) 26,27 Lewis, B.A. (3) 121 Ley, S.V. (4) 122, 172, 173, 182; (18) 137; (19) 207; (20) 60, 90 L'Hermite, G. (14) 50 Lhomme, J. (19) 309 Lhomme, L. (19) 200 Lhoste, P. (3) 236; (11) 32 Lhotak, P. (9) 61 Lhoyak, P. (16) 5 Li, A. (5) 2 Li, H. (3) 238; (4) 95,130; (19) 241 Li, H.-Y. (19) 38 Li, J. (3) 90 Li, L. (19) 22 Li, L.-S. (16) 25 Li, Q. (3) 170; (4) 95,130 Li, X. (21) 105 Li, X.-C. (7) 34; (21) 46 Li, X.-F. (21) 117 Li, X.-L. (18) 156 Li, Y.-M. (9) 32 Li, Y.-X. (18) 1
Li, Z. (18) 9, 112; (19) 161 Li, Z.-J. (3) 64, 170; (4) 95, 130 Liaigre, J. (3) 162 Liang, H.-L. (4) 131 Liang, X. (10) 93,94; (18) 38,39 Liang, X.T. (18) 37 Liao, N. (3) 289 Liao, Q.-B. (7) 7 Liao, W. (4) 161 Liberek, B. (3) 230; (10) 71-73 Lichtenthaler, F.W. (4) 188 Liese, A. (4) 191 Light, M.E. (18) 11 Lii, J.-H. (21) 2 Liljenberg, A. (21) 123 Lilly, M.D. (16) 15; (20) 87 Lim, J. (19) 89 Lin, C.-C. (3) 302 Lin, C.-H. (2) 11, 12; (4) 18, 158; ( 5 ) 29; (16) 12 Lin, H.-R. (4) 18 Lin, J. (19) 192,213 Lin, R. (19) 122; (21) 37 Lin, T.-S. (19) 277,278 Lin, W. (1) 17 Lindberg, J. (4) 116,174; (18) 140 Lindenberg, T. (4) 37 Lindhorst, T.K. (3) 73,74; (9) 23,71 Lindner, H.J. (4) 188 Ling, C.-C. (3) 41; (12) 17 Linhardt, R.J. (3) 262; (20) 142; (21) 15 Link, A. (19) 63 Linkhorst, T.K. (3) 81,82 Lintunen, T. (7) 55 Lipari, F. (20) 113 Lippa, B. (19) 20 Lippa, N. (19) 9 Liptaj, T. (18) 58,59 Liptak, A. (3) 186, 187; (4) 35, 89; (5) 17; (6) 3; (21) 24 Liu, B. (3) 275 Liu, H.-W. (9) 9; (12) 2; (20) 107 Liu, I. (19) 54 Liu, J. (9) 27; (13) 5 Liu, L. (3) 303 Liu, M. (4) 82; (18) 164; (19) 252 Liu, M.-C. (19) 277,278 Liu, M.-G. (7) 7 Liu, X. (19) 227 Liu, Y. (4) 200,209 Liu, Y.-H. (21) 82 Liv, Y. (3) 289 Live, D. (9) 26; (10) 30 Livingston, D.A. (19) 137 Livingston, P.O. (4) 150 Livingston, R.C. (3) 249; (4) 34 Lloyd, W. (19) 265 Loakes, D. (19) 39
Carbohydrate Chemistry
382 Lobazov, A.P. (21) 118 Lobbel, M. (3) 209 Locke, R.D. (4) 66, 161, 164, 165; (5) 18; (9) 55 Lockhoff, 0.(9) 59; (10) 24 Loewenschuss, A. (21) 77 Lohof, E. (3) 257 Lohray, B.B. (18) 43,49; (21) 7 Lohse, A. (10)93; (18) 39,79,80 Lois, L.M. (14) 4 Lombardo, M. (10) 80 Lonnberg, H. (19) 301,302,304 Lopenko, V.L. (7) 13 Lopez, B. (18) 105 Lopez, I. (18) 11 Lopez, J.C. (3) 6; (4) 73 Lopez, M.D. (10) 4 Lopez-Sastre, J.A. (22) 83 Lopin, C. (14) 44; (17) 9 Loretto, M.A. (9) 41 Lorthiois, E. (10) 112 Lorthois, E. (18) 91 Lou, B. (3) 9; (7) 41 Loui, M.A. (3) 7 Louis, F.F. (10) 103; (19) 129 Loupy, A. (18) 27 Lowary, T.L. (3) 220,258; (4) 71, 101; (13) 9; (18) 101 Lowe, J.B. (4) 110 Lu, A. (3) 212 Lu, Y. (3) 207; (14) 15, 19; (19) 222,223,275; (22) 84 Lubineau, A. (3) 240,271; (4) 135; (7) 61,65; (13)20; (16) 44; (20) 55,61 Lubin-Germain, N. (10) 85 Luboradzki, R. (6) 18; (21)97 Lucas, M.A. (11)37; (18) 5 Lucchini, V. (4) 212 Luedtke, N.W. (4) 115; (9) 66, 67; (18) 167, 169 Lugtenburg, J. (2) 3; (19) 36; (20) 11 Luh, T.-Y. (6) 11 Lui, B. (19) 259 Lui, D.W. (20) 106 Lui, H. (20) 103,129 Luijendijk, J. (9) 11; (19) 160 Lukomskaya, I.S. (3) 142; (20) 144 Lumbard, K.W. (3) 112 Lundquist, J.J. (3) 78; (4) 51 Lundt, 1. (18) 21, 36,53, 69,73 LUO,G.-F. (7) 7 LUO,J.-C. (10) 16 LUO,M.-Z. (19) 277,278 Luong, B.-X. (18) 71; (22) 55 Lutzen, A. (10) 41; (16) 4; (22) 77 Luyten, I. (19) 182 Lv. H.D. (20) 112 L;A, S. (21j 106
Makytruk, V.L. (10) 6 Maletic, M. (4) 123 Maliniak, A. (21) 68 Malissard, M. (3) 311 Malkar, N.B. (3) 97 Malkiewicz, A. (19) 217 Ma, B. (21) 2 Malkinson, J.P. (10) 33 Ma, L. (3) 289; (19) 269,279 Malle, B.M. (18) 36 Ma, L.T. (19) 275 Malleron, A. (3) 240; (17) 17; Ma, X. (3) 203 (20) 55,61 Ma, Y.-L. (12) 3 Mallet, J.-M. (4) 86; (18) 145, MacArthur, H.L. (18) 175 147 McCallum, C.M. (21) 8 Maltsev, S.D. (7) 47 McCarren, P.R. (4) 101 Maltseva, T. (21) 38 McCarter, J.D. (3) 213 Manabe, S. (4) 138 McClintock, J.B. (4) 143 Manbae, S. (3) 214 McCort, I. (18) 44 McDermott, B.P. (2) 32; (14) 32 Manchuk, M.N. (3) 213 Manfredi, B. (16) 51 Mach, M. (2) 30 Manfredini, S. (16) 51; (19) 40 Machida, H. (19) 82 Mang, C. (3) 257 Machytka, D. (19) 226 Mangoni, A. (12) 5 McIntee, E.J. (19) 183 Mangoni, L. (5) 20 Mackenzie, G. (22) 88 Manhas, M.S. (22) 54 McLaughlin, L.W. (19) 128 Manoharan, M. (14) 43; (19) McLeod, M.D. (9) 44 214,230,243,247-249 Macmillan, D. (3) 102 Mantovani, G. (18) 123 McPhail, A.T. (19) 136 Manzi, A.E. (1) 12 McReynolds, K.D. (21) 85 Mao, H. (18) 47 Madaj, J. (8) 15;(21) 44 Marakos, P. (8) 24 Madariaga, L. (3) 316 Marc, A. (20) 61 Maddala, R.K. (2) 16 Marceddu, T. (19)40 Mading, P. (5) 5 Marchand, A. (19) 60 Madsen, J. (5) 19; (6) 2 Madsen, R. (3) 283; (8) 19; (13) Marchase, R.B. (7) 54 Marchelli, R. (4) 210 1,28; (14) 31; (19) 134 Marchetti, S. (19) 124 Maeba, I. (19) 126 Marco, J.A. (10) 81; (22) 70 Maeda, Y. (3) 42; (9) 51 Marco-Contelles, J. (10) 66,99; Maes, E. (4) 142 (18) 90, 103, 180; (22) 15, 16 Maeshima, H. (3) 138 Marcuccio, S.M. (16) 10 Maezahi, N. (18) 1 Marcus, Y. (21) 77 Magaud, D. (3) 197 Marcusson, J. (18) 21 Magiatis, P. (9) 78 Marianucci, F. (18) 177 Magnani, J.L. (4) 117 Marini, F. (3) 111 Magnusson, G. (3) 163,168 Marino, C. (3) 34; (12) 12; (20) Magos, G.A. (21) 47 116 Magro, G. (3) 78 Mariotti, G. (3) 317 Mahalingham, A.K. (5) 12 Marquez, V.E. (19) 34, 179; (22) Mahou, M.F. (5) 31 26,27 Maier, M.A. (19)230 Marra, A. (3) 313,317, 339; (4) Maier, M.E. (18) 18 149; (10) 15; (17) 2; (18) 95 Maison, W. (10) 105 Marrero-Tellado, J.J. (3) 325; Maitani, T. (21) 120 (18) 63 Maj, K. (21) 87 Marsden, R. (4) 8 Majewski, M. (2) 7 Marsden, S.P. (3) 273; (18) 22 Majoral, J.-P. (3) 78 Marsh, A. (19) 261 Majumdar, S. (10) 101 Martens, J. (10) 105 Majzner, W.R. (19) 31 Marth, J.D. (1) 12 Makaiyama, T. (3) 137, 147 Martin, J.D. (5) 25 Maki, E. (19) 301 Martin, M.T. (19) 137 Makimura, Y. (4) 33 Martin, O.R. (3) 300,304; (10) Makino, K. (3) 204 108; (11) 5; (18) 62; (22) 31 Makiuo, K. (7)16
Lysek, R. (21) 34; (22) 53 Lyssenko, K.A. (21) 35 Lyssikatou, M. (5) 31
383
Author Index Martin, P.F. (16) 22 Martin, P.T. (7) 22; (9) 4 Martinelli, M.J. (7) 69 Martinkova, M. (3) 210; (14) 47 Martin-Lomas, M. (3) 106; (4) 148, 167; (7) 23; (18) 138, 139, 142; (21) 16 Martin-Ramos, J.D. (22) 83 Martins-Alho, M.A. (10) 89,90 Marunovic, A. (9) 5; (16) 50 Maruyama, A. (18) 152 Maruyama, M. (4) 97; (16) 36 Marwood, R.D. (3) 150;(19) 157-159 Maryanoff, B.E. (3) 263 Marzabadi, C.H. (12) 1 Marzocchi, L. (18) 102 Masjost, B. (19) 251 Masojidkova, M. (19) 173, 191 Masson, C. (13) 14 Massoui, M. (9) 4 Masubuchi, K. (19) 47 Masuda, M. (21) 71 Masuda, T. (4) 211 Masui, Y. (18) 83,93 Masuzawa, S. (3) 104 Matasuda, A. (20) 122 Math&,C. (12) 14; (19) 46,60 Matheu, I. (22) 25 Mathur, C. (22) 54 Matray, T. (19) 66 Matsuba, S. (3) 279,288,297 Matsuda, A. (3) 259,260, 307, 308; (4) 36; (14) 24; (18) 29; (19) 18,75,91,92, 110, 111, 151,155,234,235,287 Matsuda, F. (18) 104 Matsuda, H. (3) 119 Matsudo, T. (20) 132 Matsui, H. (3) 139 Matsukura, H. (22) 46,48 Matsumoto, T. (3) 286,287,292 Matsumura, S. (3) 42, 161; (9) 51 Matsuo, G. (22) 46,48 Matsuoka, K. (3) 84 Matsuoka, M. (19) 112 Matsushima, Y. (3) 127; (9) 1; (14) 20; (18) 126; (20) 137 Matsuura, K. (3) 79 Matta, K.L. (4) 66, 139, 140, 161, 163-165;(5) 18; (9) 55 Mattes, R. (20) 26 Mattila, K. (19) 304 Maugham, M.A.T. (3) 140; (11) 17 Maul, C. (18) 159 Maunier, V. (10) 22 Maurya, R. (3) 294 Mauvais, P. (3) 110; (14) 51, 53; (19) 154
Mayalarp, S.P. (3) 113 Maycock, C.D. (7) 19,20 Mayer, C. (20) 51 Mayer, J.E. (18) 170 Mayr, P. (8) 13; (10) 62; (20) 134 Mazzini, S. (19) 291 Medgyes, A. (3) 186, 187; (11) 7 Meggers, E. (19) 3 10 Mehta, G. (18) 81, 82, 121, 151, 179 Mehta, S. (4) 77 Meinander, N. (21) 78 Meinwald, J. (3) 108 Meldal, M. (3) 51; (4) 11 Meldgaars, M. (19) 5 Mele, A. (21) 90 Melean, L.G. (4) 39 Mells, K. (21) 84 Melnyk, 0.(3) 96 Melton, L.D. (4) 60 Mendez, D.B. (18) 175 Mendorca-Previato, L. (20) 118; (21) 49 Menichetti, S. (3) 188 Menozzi, M. (19) 291 Mensah, L.M. (22) 57 Menzel, A. (10) 67 Merchan, F.L. (19) 282-284 Mereyala, H.B. (2) 16; ( 5 ) 30; (13) 22; (22) 21,22 Merino, P. (19) 282-284 Merritt, J.R. (8) 19 Messanga, B.B. (3) 130 Messere, A. (19) 236 Messina, R. (14) 1 Meuillet, E.J. (18) 143, 144 Meyerhoff, M.E. (1) 14 Meyers, A.I. (18) 110 Meyyappan, M. (10) 110,112; (18) 91 Miao, Z.-W. (19) 61 Michalik, D. (2) 24,25 Michalik, M. (8) 9; (10) 98; (14) 57, 58; (21) 66 Michalski, J. (19) 195 Micuch, P. (10) 100; (14) 21; (22) 64 Mierzwa, R. (4) 177 Miesch-Gross, L. (9) 39 Miethchen, R. (6) 17; (8) 8; (10) 55, 56,60 Mikata, Y. (16) 30 Mikazaki, T. (4) 67; (20) 97 Mikhailopulo, I.A. (19)202 Mikhailopulo, I.G. (19) 57 Mikhailov, S.N. (19) 182 Mikhura, I.V. (7) 8 Mikkelsen, L.M. (4) 90 Mikkola, S. (19) 302 Mikros, E. (21) 13 Milecki, J. (21) 38
Miletich, M. (20) 38 Milius, W. (21)93 Millar, M.J. (18) 108 Miller, A.D. (4) 172 Miller, J.A. (11) 1; (19) 84-86 Miller, M.J. (19) 241 Miller, S.L. (2)47 Miller-Podraza, H. (4) 21 Millquist-Fureby, A. (3) 27; (20) 1 Min, B.-S. (7) 33 Min, J.M. (19) 272,273 Minakawa, N. (19) 18,234,287 Minatagawa, T. (3) 288 Minch, M.J. (21) 8 Minke, W.E. (10) 26 Mintas, M. (9) 5; (16) 50 Mioskowski, C. (3) 53; (20) 109 Miquel, N. (3) 306,319 Miroshnikov, A.I. (19) 266 Mishra, P.K. (19) 7 Misiura, K. (19) 31 Misoi, R. (21) 54 Misra, A.K. (4) 110 Mitaku, S. (8) 24 Mitchell, F. (21) 106 Mitchell, H.J. (1) 17, 18; (3) 132; (4) 2-5; (11) 38-40; (12) 6-8; (14) 10,28 Mitchell, M.B. (3) 51; (10) 79 Mitsuda, S. (19) 258; (20) 81 Mitsui, T. (19) 64 Mitsuki, M. (20) 96 Mitsutomi, M. (7) 31; (20) 79 Mitsuya, H. (19) 112 Miura, S. (19) 82 Miura, Y. (20) 96 Miwa, M. (19)47 Miyagoshi, H. (19) 144 Miyahara, T. (7) 77 Miyajima, K. (9) 72 Miyamoto, S. (2) 36; (3) 152; (21) 65 Miyamoto, T. (4) 127,129 Miyasaka, T. (19) 119 Miyashiro, H. (7) 33 Miyashita, T. (19) 225 Miyata, T. (3) 174 Miyauchi, M. (18) 84, 85,92 Miyazaki, T. (19) 258; (20) 81 Miyazawa, M. (18) 57 Miyoshi, D. (1) 19 Mizuno, K. (18) 117 Mizuno, M. (3) 154; (4) 43, 149; (7) 46 Mizuno, T. (21) 89 Mizushima, Y. (11)24 Mlaker, E. (18) 31 Mo, H. (4) 217 Mo, X. (5) 2 Mobashery, S. (18) 164; (19) 252
Carbohydrate Chemistry
384 Mochizuki, T. (3) 181, 182; (5) 1; (7) 52; (20) 110 Moeller, K.D. (16) 38 Mohal, N. (18) 81,82,151 Moineau, C. (3) 245; (10) 13 Molina, J.L. (10) 47,97; (19) 21 Moller, B.L. (3) 141 Molnar-Perl, I. (21) 100 Molyneux, R.J. (18) 32 Momany, F.A. (4) 190; (21) 10, 11 Momose, T. (22) 9 Monaco, P. (3) 216 Monneret, C. (4) 87; (7) 62; (9) 63; (18) 46; (19) 70 Monnier, V.M. (8) 15 Montana, M.A. (19) 164 Monteiro, C. (21) 55 Montenegro, G. (3) 56 Montero, E. (3) 219; (21) 53 Montero, J.-L. (2) 19; (17) 5 Montesano, V.J. (2) 26; (10) 82 Montesarchio, D. (19) 236 Montgomery, J.A. (19) 35,41, 81 Monti, D. (4) 85 Moon, S.C. (18) 115 Mooradian, D.L. (1) 14 Mootoo, D.R. (3) 132,309; (21) 14 Moracci, M. (20) 50 Moraga, E. (17) 22 Morawietz, M. (16) 37 Modre, A. (2) 19; (17) 5 Morgaan, A.E.A. (10) 87 Mori, H. (4) 30; (20)4 Mori, K. (19) 144,225 Mori, Y. (7) 31; (20) 79 Moriguchi, T. (19) 152, 181 Morikawa, T. (3) 119; (18) 107, 109 Morin, C. (5) 9,23; (8) 25 Morio, K.4. (3) 330,331; (19) 130,131 Morisaki, N. (18) 132 Morishima, H. (10) 7 Morita, K. (18) 132 Moro, S. (19) 179 Moroz, 0.(4) 31; (20) 52 Morston, R.W. (18) 26 Mortreux, A. (22)90 Mota, A. (19) 62; (22) 66 Motawia, M.S. (3) 141 Motoyoshi, H. (22) 32 Moule, C.J. (9) 48 Mounski, T.F. (3) 123 Mourier, N. (19) 280 Moutinho, P. (2) 20; (19) 121 Mower, K. (22) 56 Mowery, K.A. (1) 14 Moyroud, E. (19)45
Mozdziesz, D.E. (19) 277,278 Mueller, R.H. (19) 164 Miigge, C. (4) 166 Muhlman, A. (16) 9 Mukai, C. (19) 295 Mukai, H. (18) 153 Mukaiyama, T. (3) 138, 176; (4) 40,41,45 Mukerjea, R. (20) 128 Mukhapadhyay, B. (3) 32 Mukherjee, A. (4) 96; (5) 6; (12) 11; (20) 120 Mukherjee, I. (4) 96 Mukhopadhyay, A. (17) 19,24; (21) 17 Mukhopadhyay, R. (10) 101; (22) 51 Mulard, L.A. (4) 47, 145-147 Mullard, L.A. (3) 149 Muller, B. (16) 34; (18) 173; (19) 205 Muller, D. (4) 27; (20) 17 Muller, E. (10) 43; (19) 32 Muller, M. (1) 5; (3) 4; (4) 7 Munakata, R. (22) 76 Muiioz, J.L. (21) 16 Munoz-Letelier, C. (22) 34 Murakami, A. (18) 117 Murakami, H. (3) 222; (4) 193, 194; (20)24,25,31 Murakami, T. (22) 71 Murasaki, C. (19) 47 Murata, K. (3) 125 Murata, T. (3) 166; (20) 37 Murga, J. (10) 81; (22) 70 Murphy, P.V. (15) 1 Murray, B.W. (19) 207; (20)90 Murthy, C.V.S.R. (13) 15 Murugaiah, A.M.S. (2) 28; (22) 36 Musicki, B. (3) 110; (14) 50-53 Mynarski, J. (3) 51 Mynott, R. (3) 133 Myszka, H. (3) 47 Nacro, K. (22) 26,27 Nagai, H. (3) 161 Nagai, N. (21) 58 Nagamatsu, Y. (21) 104 Nagamitsu, T. (3) 104 Naganawa, H. (4) 157 Nagano, C. (13) 12 Naganogowda, G.A. (4)69 Nagaoka, T. (3) 20 Nagaraj, R.(3) 323; (9) 14 Nagaregawa, Y. (4) 127 Nagata, T. (19) 189 Nagl, A. (9) 5; (16) 50 Nagy, V. (10) 48,49 Nahara, T. (12) 3
Nahraman, N. (21) 114 Nahro, J. (3) 267 Naili, S. (22)90 Nair, B.G. (4) 61 Nair, L.G. (3)44,(4) 83; (9) 7; (10) 57 Nair, M.G. (18) 170 Nair, R.V. (19) 257 Nair, V. (4) 84; (9) 80; (14) 11, 59; (18) 165; (19) 95, 166, 274; (20) 77 Naito, T. (18) 70 Nakagawa, R. (19) 295 Nakagawa, T. (3) 148; (18) 13 Nakahara, Y. (3) 103,214; (4) 14, 54,70, 138, 162, 170; (10) 29 Nakai, H. (4) 189; (20) 30 Nakai, M. (10) 77 Nakai, T. (3) 326; (22) 50 Nakai, Y. (3) 26 Nakajima, H. (7) 32; (20) 96, 114 Nakajima, M. (10) 37 Nakama, T. (4) 138 Nakamoto, K. (4) 111 Nakamura, A. (21) 104 Nakamura, H. (9) 19; (16) 7 Nakamura, K. (4) 14 Nakamura, K.T. (19) 119 Nakamura, M. (19) 150 Nakamura, N. (7) 33 Nakamura, S. (4) 65 Nakamura, T. (16) 18; (21) 57 Nakamura, Y. (9) 42 Nakano, H. (3) 222,223; (4) 193, 194; (7) 32; (19) 64; (20) 24, 25, 31,39, 114 Nakano, M. (10) 7 Nakano, T. (18) 130; (20) 143 Nakase, Y. (4) 52 Nakata, T. (22) 46,48 Nakatani, Y. (21)48 Nakatsu, N. (18) 132 Nakatsubo, F. (7) 24 Nakayama, H. (7) 42,43 Nakayama, S.-Z. (3) 281 Nakazawa, H. (19) 295 Nakazawa, I. (21) 71 Nampalli, S. (19) 39 Nan, F. (18) 136 Nanai, S. (7) 52 Nandanan, E. (19) 179 Nan du Padt, A. (20) 115 Nango, E. (18) 126; (20) 137 Nara, S. (18) 104 Narasimhamurthy, S. (4) 69 Narayanareddy, K. (18)49; (21) 7 Narita, K. (18) 130;(20) 143 Narsaiah, A.V. (6) 12
385
Author Index Narumi, S. (13) 12 Nash, R.J. (18) 32,84-86,92 Nasr, A.Z. (10) 87 Nativi, C. (3) 188 Natsch, S. (15) 3; (19) 208 Naundorf, A. (15) 3; (19) 208 Nazimov, I.V. (21) 118 Neelamkavil, S. (19) 50 Nelson, J.A. (3) 111 Nemr, A.E. (22) 65 Nenajdenko, V.G. (3) 8 Nerome, K. (10) 39 Net, G. (11)30; (17) 8; (22) 92, 94,98,99 Neuvonen, K. (19) 302 Newton, M.G. (14) 30; (19) 96 Neyret, S. (21) 55 Nguyen, C.H. (19) 70 Nguyen, H. (2) 4 Nguyen, O.T.K. (11)37; (18) 5 Nguyen-Ba, N. (19) 28 1 Nguyen-Kim, P.-P. (19) 105 Nhien, A.N.V. (9) 35; (14) 26 Niazimbetova, Z.I. (14) 38 Nicholas, G.M. (3) 123 Nicolaou, K.C. (1) 17, 18; (3) 90, 132,143; (4) 2-5, 17; (9) 25; (11) 38-40, (12) 6-8; (13) 6; (14) 10,28 Nicotra, F. (3) 270; (7) 11; (18) 52 Nidetzky, B. (8) 13; (10) 62; (20) 134 Nie, R.-L. (3) 207; (14) 19 Niehaus, H. (19) 305 Nielsen, C. (19) 27,118 Nielsen, P. (19) 106,114,218 Nierengarten, J.-F. (3) 76 Nieto, 0.(3) 56 Nieto, P.M. (4) 148; (18) 139; (21) 16 Nifant’ev, N.E. (4) 75, 128; (7) 49 Nifantiev, E.E. (21) 35 Nikaido, 0.(19) 244 Nikam, P.S. (21) 96 Nikath, M.A. (2) 40 Nikolaev, A.V. (4) 119 Nilsson, B.L. (19) 237 Nilsson, M. (3) 183; (9) 74 Nimtz, M. (4) 29; (20) 35 Ning, J. (19) 23 Ninomiya, I. (18) 70 Nishi, N. (3) 139; (4) 114 Nishida, M. (18) 84,85,92 Nishida, Y. (3) 164; (4) 74; (20) 57 Nishijima, M. (3) 181, 182; (7) 52 Nishikawa, A. (18) 132 Nishikawa, Y. (8) 15
Ogier, L. (5) 23; (8) 25 Oh, C.-Y. (18) 75 O’Hanlon, P.J.(22) 57 Ohashi, Y. (3) 292 Ohbu, K. (3) 218 Ohe, K. (22) 100 Ohgami, T. (18) 168 Ohigashi, H. (18) 117; (22) 68 Ohita, K. (11) 24 Ohkubo, K. (18) 1 Ohkubo, M. (10) 7 Ohlsson, J. (3) 163, 168 Ohmori, K. (3) 109,205,292 Ohmura, Y.(19) 295 Ohnishi, Y.(3) 232; (4) 170 Ohno, S. (21) 92 Ohno, T. (19) 150 Ohrlein, R. (4) 110; (10) 67; (20) 62 Ohrui, H. (3) 109,162, 165; (6) 1; (18) 3; (19) 112 Ohta, H. (19) 258; (20) 81 Ohtake, H. (3) 136; (7) 78; (18) 155,156 Ohtake, Y. (12) 4 Ohtake, Y.U. (3) 295 Ohtsuka, E. (19) 244 Ohtsuka, I. (4) 76 Ohtsuki, K. (18) 168 Oikawa, M. (3) 180; (9) 73 Oishi, M. (21) 109 Oishi, T. (3) 134 Oivanen, M. (19) 301,302,304 Ojala, C.R. (10) 1; (21) 91 Ojala, W.H. (10) 1; (21) 91 Ojika, M. (3) 124 Okada, Y. (4) 194; (14) 46; (20) 24 Okado, Y. (22) 14 Okami, Y. (10) 37 Okamoto, A. (3) 295; (12) 4 Okamoto, K. (7) 32; (20) 114 Okazaki, M. (3) 118 Oki, T. (4) 99 Obaje, O.J. (21) 41 Oku, T. (5) 1; (12) 10; (20) 110, 111 Obendorf, R.L. (3) 121 Okunishi, M. (19) 295 Oberdorfer, F. (8) 6 Okuyama, K. (19) 203; (20) 104; Obi, K. (19) 155 (21) 92 Obika, S. (3) 330,331; (19) 117, 130,131 Olano, D. (9) 22 Olgen, S. (14) 30; (19) 96,279, OBoyle, K.M. (15) 1 Ochiai, K. (3) 295; (12) 4 296 Olschimke, J. (4) 88 O’Doherty, G.A. (2) 4,5; (3) 296; (16) 2 Olsen, A.G. (19) 118 Oertel, K. (10) 34 Olsen, C.E. (3) 141; (19) 109, Ogasawara, K. (2) 8,9; (14) 49 115 Olsson, A.I. (21) 123 Ogawa, K. (4) 72; (21) 59 Ogawa, S.(3)211,212,219; (18) Olsson, L. (3) 44, (9) 7; (10) 57 107, 109,152; (20) 56; (21) Omura, S. (19) 161 53 Ondrus. V. (22) 64 Ogawa, T. (3) 180; (4) 70; (9) 73 ONeil, I.A.(19) 90
Nishimura, N. (19) 126 Nishimura, S.-I. (4) 215; (10) 7 Nishimura, T. (10) 7 Nishimura, Y. (9) 19; (10) 36,37, 39; (16) 7 Nishio, T. (5) 1; (12) 10; (20) 110, 111 Nishiyama, T. (10)42 Nishizono, N. (4) 84; (9) 80; (18) 165 Nitz, M. (4) 61 No, Z. (19) 29 Nogami, Y. (4) 188 Noguchi, K. (21) 92 Noguchi, T. (19) 203; (20) 104 Nogueras, M. (10) 4 Nohara, T. (4) 58 Nojiri, H. (21) 109 Nolting, B. (4)44,63; (16) 45,46 Nomizu, M. (4) 114 Nomura, E. (18) 117 Nomura, M. (19) 75,91 Nonaka, K. (19) 37; (20) 131 Norberg, T. (3) 183; (9) 74; (20) 98; (21) 30,31 Norbert, P. (21) 23 Norgard-Sumnicht, K. (1) 12 Norris, P. (8) 20 North, J.T. (19) 164 Norwood, T.J. (21) 25 Note, R. (19) 70 Notenboom, V. (3) 43 Novo, B. (8) 10 Nowacki, A. (10) 18 Nowak, P. (2) 7 Noya, B. (22) 28 Nozato, N. (3) 295; (12)4 Nuhn, P. (3) 75 Numata, Y. (21) 58 Nutt, R.F. (22) 79 Nuzillard, J.-M. (2) 23; (10) 106 Nyberg, N.T. (4) 144
386 Onishi, T. (19) 295 Ono, A. (19) 37; (20) 131 Ono, H. (7) 31; (20) 79 Ono, M. (9) 43 Ono, N. (19) 295 Onodera, J.4. (3) 279,288,297 Oogo, Y. (19) 37; (20) 131 Opatz, T. (3) 234; ( 5 ) 11 Oretskaya, T.S. (19) 250 Orgel, L.E. (19) 12 Oritani, T. (19) 196 Ortiz-Mellet, C. (9) 20,21,64, 65; (10) 45,46 Ortner, J. (3) 144; (8) 4; (20)40; (21)67 Osborn, H.M.I. (3) 36, 175; (9) 38 Osborn, J. (21) 5 Oscarson, K. (16) 8 Oscarson, S. (3) 131; (4) 59, 116, 153, 156, 174; (18) 140 Ostman, J.M. (10) 1; (21) 91 Osumi, K. (22) 35 Otaya, K. (18) 57 Otsubo, N. (3) 199; (4) 179 Otsuka, M. (3) 127; (9) 1; (14) 20 Ott, A.-J. (4) 44; (16)45 Ouchi, H. (3) 42 Ourisson, G. (2 1) 48 Oustedal, D.O. (7) 36 Ouwerkerk, N. (2) 3; (19) 36; (20) 11 Ovaa, H. (17) 11 Ovcharenko, V. (21) 81 Overkleeft, H.S. (3) 152; (21) 65 Owen, D.J. (3) 241; (11) 16 Owens, S.R. (19) 248,249 Ozaki, H. (19) 77 Ozawa, T. (18) 104 Ozawa, Y. (4) 124; (16) 31 Ozores, L. (22) 28
Palmery, M. (5) 7 Palmieri, S. (3) 227 Palmisano, G . (4) 195; (21) 101 Palozza, P. (16) 51 Palumbo, G . (12) 9 Pamies, 0.(11) 3 0 (17) 7,8,26; (22) 92-95,98,99 Pan, Q. (4) 108, 175 Panda, J. (14) 18; (22) 18 Panday, N. (10) 109-111 Pandey, G. (18) 56 Pani, A. (19) 40 Pankiewicz, K.W. (8) 5; (19) 55 Panza, L. (3) 173,231; (4) 53, 195; (7) 48; (20) 72,73; (21) 101 Paoletti, S. (20) 38 Papireddy, P. (18) 49; (21) 7 Papot, S. (3) 54 Pappalardo, M.S. (3) 231 Paquette, L.A. (3) 126 Parada, J. (17)22 Paredes, M.D. (22) 28 Park, E.H. (19) 42 Park, H. (7) 14 Park, H.G. (7) 28; (20) 83 Park, K.H. (18) 40 Park, M. (19) 33 Parkanyi, L. (11) 8 Parker, K.A. (3) 280,290 Parker, W.B. (19) 81 Parolis, H. (1) 29 Parrish, J.P. (7) 1 Parrot-Lopez, H.P. (4) 213; (10) 25 Parsch, J. (3) 327 Parsons, S.F. (18) 68; (20) 12 Paschal, J.W. (3) 115 Pasquarello, C . (3) 311 Passacamtilli, P. (3) 189 Pasti, C. (17) 2 Pastuch, G. (3) 190; (11) 18 Patel, M. (4) 177 Pacic, M.M. (4) 49 Patel, N. (21) 25; (22) 33 Packwood, J. (4) 26; (20) 16 Patel, P. (21) 88 Patel, R.N. (19) 164 Pagliari, S. (4) 210 Pathak, D. (9) 18 Pai, B. (19) 16 Pathak, T. (9) 33 Painter, G.F. (18) 54 Patil, N.T. (16) 47 Painter, G.R. (21) 39 Patoprsty, V. (21) 81 Pakhomova, S. (9) 15 Patrick, B. (11) 12 Pal, A. (22) 51 Patro, B. (3) 310 Pal, S. (4) 120 Patterson, S.E. (19) 14 Palacios, J.C. (16) 6; (18) 11 Palazzino, G. (5) 7 Patton, J.T. (4) 117 Palcic, M.M. (3) 212; (4) 23; ( 5 ) Paul, B.J. (8) 4; (21) 67 6; (12) 11; (20) 4,58,63, 120 Pazynina, G.V. (4) 80 Pale-Grosdemange, C . (14) 3,4; Pean, C . (4) 207 Pearce, A.J. (4) 86,197; (18) 146, (18) 2 147 Paleta, 0.(5) 26 Pearson, A.J. (15) 5 Palmacci, E.R. (3) 157 Pearson; W.H: (22) 60 Palmer, A.M. (18) 55
Carbohydrate Chemistry Pechenov, A.E. (19) 266 Pedotella, S. (12) 9 Pedrosa, M.T.C. (9) 62 Peeters, K. (18) 47 Peilstocker, K. (4) 112, 113 Peixoto, C. (14) 53 Pelczer, I. (4) 123 Pellacini, F. (19) 280 Pelter, A. (5) 26 Peiia, M.A. (21) 94 Peng, J. (7) 54 Pkez, C . (19) 97 Perez, R. ( 5 ) 25 Perez, S. (1) 8; (21) 1, 13 Perez-Balderas, F. (4) 199 PCrez Baz, J. (19) 162 PQez-Pkrez, M.J. (7) 70; (19) 97, 98 Perfil'Eva, E.S. (21) 35 Peri, F. (3) 270; (7) 11; (10) 65; (11) 4; (18) 52, 123 Pkrik, J. (9) 16 Periers, A.-M. (3) 110; (14) 50-52 Perigaud, C . (19) 185 Perkkalainen, P. (21) 76 Perly, B. (4) 207 Perol, N. (3) 192 Perrin, V. (4) 50; (20) 28 Perrone, C.C. (7) 5 Persky, R. (18) 23 Perugino, G. (20) 50 Peseke, K. (2) 24,25; (10) 98; (14) 57, 58 Peterfly, K. (3) 186 Peter-Kataline, J. (21) 119 Peters, J.A. (18) 8 Peters, T. (3) 195; (21) 26, 50 Petersen, B.O. (18) 80; (20) 70, 123; (21) 60 Petersen, M. (19) 106, 116 Peterson, M.A. (19) 99,237 Petillo, P.A. (3) 80; (4) 56, 186; (9) 54 Petraud, M. (21) 23 Petrov, D.D. (19) 299 Petrovic, J. (22) 20 Petrus, L. (2) 38; (3) 254; (14) 8; (18) 28; (21) 81 Petruskova, M. (3) 254; (18) 28 Peyrottes, S. (19) 185 Pfahler, C . (15 ) 6 Pfannenstiel, T.J. (17) 4; (20) 124 Pfefferkorn, J.A. (3) 143 Pfleiderer, W. (19) 215 Pfundheller, H.M. (19) 109 Pham, L.H. (4) 166 Pham-Huu, D.-P. (3) 254; (18) 28 Phizicky, E.M. (19) 167
387
Author Index Phkohchi, N. (3) 165 Phoon, C.W. (18) 176 Piancatelli, G. (3) 189 Piao, Z. (19) 269 Picard, M.A. (3) 58 Picasso, S. (3) 311; (18) 88 Piccialli, G. (19) 236 Picton, M.R. (14) 41; (22) 10 Piedade, F. (14) 17 Piekarska-Bartoszewicz, B. (21) 32 Piepersberg, W. (20) 92 Pierce, A. (8) 24 Pierra, C. (19) 296 Pierre, C. (14) 52 Pietrzkoeski, Z. (19) 17 Piettre, S.R. (14) 44; (17) 9 Pignot, M. (11) 21; (19) 87 Pihlaja, K. (21) 81 Piitari, S. (19) 302 Pillon, M. (9) 35; (14) 26 Pin, J.-P. (9) 50 Pinna, L. (18) 102 Pinto, B.M. (3) 235; (4) 107,136; (10) 2, 12; (11) 12, 13; (20) 123; (21) 60 Piskorz, C.F. (4) 66, 140, 163, 164; ( 5 ) 18; (9) 55 Pissarnitski, D. (3) 126 Pistara, V. (18) 119 Pistia, G. (18) 61 Pitkanen, I. (21) 76 Pitsch, S. (19) 114,253 Pittard, B. (18) 12 Planker, E. (3) 257 Plante, O.J. (3) 156, 157 Plantier-Royon, P. (2) 23; (3) 248; (8) 7; (10) 106; (14) 36 Plass, M. (21) 32 Platt, F.M. (18) 33 Platz, G. (21) 93 Plavec, J. (3) 71; (21) 36 Plaza, M.T. (3) 298; (19) 62; (20) 69; (22) 66 Plaza-Lopez-Espinosa, M.T. (11) 11 Plenkiewicz,J. (12) 13 Plesner, I.W. (10) 93; (18) 39 Plettenburg, 0.(18) 129 Pljevaljcic, G. (11) 21; (19) 87 Plou, F.J. (20) 67 Plusquellec, D. (3) 30,31 Podkidysheva, E.I. (3) 142; (20) 144 Podlaha, J. (9) 30 Poerra, C. (19) 279 Poggendore, P. (10) 67 Pohlentz, G. (3) 145 Poigny, S. (22) 34 Poirot, E. (21) 16 Poitout, L. (18) 30
Polanc, S. (3) 71 Polat, T. (3) 262; (21) 15 Polchow, K. (11)2 Poletti, L. (4) 53; (7) 48; (20) 73 Pollicino, S. (10) 65; (11)4; (18) 123 Pongracz, K. (19) 66 Pons, J.-M. (19) 108 Pontikis, R. (19) 70 Poopeiko, N. (19) 78 Pope, A.J. (22) 57 Popenda, M. (19) 193 Popkovich, G.B. (21) 118 Popsavin, M. (3) 321; (19) 125; (22) 20 Popsavin, V. (3) 321; (19) 125; (22) 20 Porcari, A.R. (19) 44 Portella, C. (2) 23; (3) 248; (8) 7; (10) 106;(14) 36 Portoles, R. (10) 81 Porwanski, S. (3) 236; (6) 5; (11) 32 Postel, D. (6) 9; (7) 56; (9) 35; (11) 23; (14) 26 Postema, M.H.D. (3) 303 Poszgay, V. (21) 63 Potier, P. (20) 82 Potrzebowski, M.J. (19) 31 Potter, B.V.L. (3) 150, 151,255; (18) 128; (19) 157-159 Poulenat, G. (9) 54 Pouli, N. (8) 24 Poupon, E. (18) 71; (22) 55 Pouysegu, L. (21) 23 Poveda, A. (1) 26; (21) 15 Powell, W.S. (22) 69 Powis, G. (18) 136, 143, 144 Pozsgay, V. (3) 186, 187; (4) 185 Pradera, M.A. (9) 22; (10) 47 Pradbe, J.-P. (3) 162; (19)290 Pradero, M.A. (19) 21 Prado, F. (10) 84 Prado, M.A.F. (6) 8; (9) 62 Prado, R.F. (9) 62 Prahl, I. (4) 178 Prajapati, D. (9) 18 Prakash, T.P. (19) 248,249 Praly, J.-P. (1) 27; (2) 33; (4) 5 0 (10) 83; (20) 28 Pramanik, B. (4) 177; (19) 136; (21) 82 Prandi, J. (1) 18; (4) 100, 133; (14) 22; (18) 99 Prange, T. (2) 37; (3) 299 Prasad, T.R. (5) 12 Prasuna, G. (18) 43,49; (21) 7 Pratap, R. (19) 123 Preiss, A. (4) 166 Premasthira, C. (22) 68 Premkumar, M. (18) 49; (2 1) 7
Prestat, G. (19) 290 Preswich, G.D. (7) 54 Previato, J.O. (20) 118; (21) 49 Previtera, L. (3) 216 Prezeau, L. (9) 50 Prhavc, M. (14) 43; (19) 243 Prickett, M.P. (3) 69 Priebe, W. (13) 16 Prikrylova, V. (20) 135 Prinzbach, H. (18) 125 Pritchard, G.J. (19) 127 Proia, R.L. (1) 11 Pronayova, N. (18) 58,59 Prosperi, D. (7) 48 Prudhomme, D.R. (19) 33 Ptak, R.G. (19)9,44 Puccioni, L. (6) 7; (9) 37 Pugh, A.W. (11) 1; (19) 84-86 Puignou, L. (21) 121 Pullockaran, A.J. (19) 164 Puranik, R. (2) 13; (6) 16; (13) 23 Pysowski, J. (19) 171 Qi, H. (8) 16 Qi, M. (21) 117 Qi, T. (3) 124 Qi, Y. (19) 25 Qiao, L. (18) 136, 143, 144 Qing, F.-L. (19) 93 Qiu, Q.-R. (19)2 Qiu, Y.-L. (19) 38,293 Quagliotto, P. (10) 19 Quartey, E.G.K. (10) 103 Quelch, K.J. (9) 60; (16) 24 Queneau, Y. (3) 217; (6) 5; (16) 39,40; (20) 82 Qui, W.-R. (20) 86 Quiclet-Sire, B. (7) 74; (18) 118; (19) 260 Quigley, P.F. (18) 26 Quijano, M.L. (10) 4 Quinsac, A. (3) 272 Raap, J. (2) 3; (19) 36; (20) 11 Rabiller, C. (20) 26 Raczko, J. (10) 67 Rademacher, T.W. (4) 148; (18) 139 Radic, L. (3) 321 Radkowski, K. (3) 133 Radmer, M.R. (19) 183 Ragg, E. (19) 291 Ragupathi, G. (4) 150 Raheem, M.A. (18) 49; (21) 7 Rahman, M.M.A. (22) 30 Rai, K.M.L. (2) 40 Raic-Malic, S. (9) 5; (16) 50 Raimondi, L. (21) 64 Raina, S. (22) 29
388 Rainer, J.D. (3) 269 Rajwanshi, V.K. (19) 114,116, 118 Rakb, J. (10) 58 Rakotoarisoa, H. (3) 250; (13) 11 Ramamurthy, V. (22) 84 Ramana, C.V. (10) 96 Ramasamy, K.S. (3) 328; (19) 11,240 Ramesh, S.S. (18) 179 Ramirez-Fernhdez, A. (11) 11 Ramon, D.J. (14) 13 Ramos, D. (10) 32 Ramos, M.L. (17) 21; (21) 73 Randell, K.D. (4) 107, 136; (10) 2, 12; (11) 13 Rangappa, K.S. (2) 40 Rao, C.P. (17) 19,24; (21) 17 Rao, I.M. (18) 170 Rao, M.H.V.R.(2) 35; (3) 338; (18) 24 Rassu, G. (18) 102 Rastall, R.A. (4) 26; (20) 16 Ratier, M. (21) 23 Rauter, A. (14) 17 Ravikanth, V. (3) 323 Ravikumar, V.T. (19)224 Ravindran, B. (9) 33 Ravindranathan, S. (21) 40 Rawlings, B.J. (21) 25 Rayner, B. (19) 232 Readman, S.K. (3) 242,273; (18) 22 Readshaw, S.A. (9) 2 Reddy, B.V.S.(5) 13, 15; (13) 15; (22) 36 Reddy, G.B.S.(16) 13 Reddy, K.R. (2) 16; (5) 30; (13) 22 Reddy, R.E. (3) 91 Reddy, V.G. (2) 35 Reddy, V.P. (8) 15 Redgrave, A.J. (3) 7 Redmond, J.W. (10) 86 Reed, J.K. (19) 199 Rees, D.C. (22) 81 Reese, C.B. (19) 227,265 Regan, A.C. (14) 45; (17) 10; (19) 194 Rege, S.D. (3) 91 Regenbogen, A.D. (2) 36; (3) 152; (21) 65 Reichel, F. (3) 98 Reid, S.P. (20) 51 Reilly, P.J. (21) 4 Reiner, J.E. (22) 79 Reiner, M. (3) 200 Reiner, T. (19) 215 Reinhoudt. D.N. (21) 97 Reinke, H.(6) 17;(10) 55,56,60;
Carbohydrate Chemistry (14) 58 Reipen, T. (4) 13; (10) 28 Reither, V. (19) 239 Ren, H. (21) 117 Rendle, P.M. (7) 2 Renneberg, B. (9) 32 Renouf, D.V. (21) 61 Rentsch, D. (21) 72 Renzi, G. (18) 177 Repetschnigg, W. (21) 67 Resnati, G. (8) 10 Restrepo-Sanchez, N. (18) 120 Reymond, J.-L. (18) 106 Reynolds, W.F. (21) 47 Rhee, H. (19) 140-142 Rhee, J.S. (3) 171; (20) 36 Rheingold, A.L. (14) 38 Ribeiro, A.A. (19) 229 Ricci, A. (18) 123 Ricci, M. (3) 316 Richards, J.C. (4) 93; (20) 89 Rideout, J.L. (18) 19; (19) 271 Riekkola, M.-L. (21) 103 Riess, J.G. (3) 1; (5) 8 Riley, A.M. (3) 255; (18) 128; (19) 158 Rinaldi, P. (8) 15 Risley, J.M. (10) 23 Risse, S. (9) 63 Rivas, E. (3) 56 Rizzo, C.J.(19) 33 Ro, J. (16) 1 Robert, M.J. (4) 8 Roberts, B.P. (6) 15 Roberts, C.S. (4) 8; (8) 19 Roberts, S.M.(18) 26 Robia, I. (18) 96 Robina, I. (14) 56 Robins, M.J. (2) 20; (19) 99, 121, 237 Robles, R. (19) 62; (22) 66 Robyt, J.F. (20) 32,128 Rodionov, A.A. (19) 182 Rodrigues, P. (3) 271 Rodriguez, C. (19) 62 Rodriguez, J.B.(19) 163 Rodriguez, J.F. (18) 76; (19) 108 Rodriguez, M. (3) 298; (20) 69 Rodriguez, R.M. (1) 17, 18; (3) 132; (4) 2-5; (11)38-40; (12) 6-8; (14) 10,28 Rodriguez-Amo, J.F. (2) 1; (22) 83 Rodriguez-Fernandez, M. (10) 99 Roehrig, S. (10) 69 Roelofsen, A.M. (3) 98 Roets, E. (19) 311 Rogel, 0.(17) 6 Rohdich. F. (19) 212; (20) 95 Rohmer,'M. (14) 2-4; (18) 2,4
Rokach, J. (22) 69 Roland, A. (19) 177; (22) 1 Roldan, V.P. (18) 7 Rollin, P. (3) 227,272; (6) 4; (10) 32; (11)5; (18) 62 Roman, E. (22) 43 Romanova, E.A. (19) 250 Romeo, R. (3) 231 Romero, A. (20) 8; (22) 62 Romero, I. (3) 46 Romero Millan, F. (19) 162 Romieu, A. (10) 43; (19) 32 Rommens, C. (3) 96 Ronco, G. (6) 9; (7) 56; (9) 35; (11) 23; (14) 26; (22) 88 Rong, S. (18) 143 Ronnberg, B. (4) 144 Ronsisvalle, G. (3) 231 Roos, J. (9) 40 Roos, Y.H. (21) 78 Roper, H.(10) 81 Rosair, G.M. (22) 81 Rose, D.R. (3) 43 Roselli, G. (18) 177 Rosemeyer, H. (19) 202 Rosenberg, H.J. (3) 255 Rosenberg, I. (19) 173, 191 Rosenski, J. (19) 182 Ross, A.J. (4) 119 Rosseau, B. (20) 109 Rossi, J.-C. (22) 1,2 Rossi, M. (20) 50 Rossoni, G. (16) 51 Rothe, U. (4) 109 Roupioz, Y. (19) 309 Roush, W.R. (4) 151 Rousseau, B. (3) 53 Rousseau, C. (3) 300; (22) 31 Roussel, F. (7) 15 Roussel, M. (3) 30 Roussev, C.D. (19) 299 Roy, N. (3) 32; (4) 96 Roy, R. (1)24; (3) 208,225,267, 275; (4) 33,216; (5) 10; (16) 35 Roy, S.K. (19) 245 Rozenberg, M. (21) 77 Ruasse, M.F. (13) 7 Ruda, K. (4) 116, 174; (18) 140 Rudenko, V.N. (2) 44,45 Ruhela, D. (4) 106 Ruiz, A. (11)30; (17) 7, 8,26; (22) 92-95,98,99 Ruiz-Calero, V. (21) 121 Rukhman, I. (3) 114 Russ, P. (19) 179 Russo, G. (3) 173; (4) 53; (20) 72, 73 Rutherford, T.J. (3) 242 Rybar, A. (10) 104 Rybcynski, P.J. (21) 72
389
Author Index Ryder, N.S. (9) 77 Ryuo, K. (15) 4 Saak, W. (10) 105 Saavedra, J.E. (1) 14 Saavedra, O.M. (3) 52 Sabatino, P. (10) 65; (11) 4 Sadalapure, K. (3) 81, 82; (9) 23, 71; (22) 36 Saegusa, H. (22) 6 Siigi, G. (19) 226 Saha, G. (22) 69 Saha, N.N. (22) 42 Sahai, P. (18) 111 Sahara, H. (11) 24 St. Hilaire, P.M. (3) 51; (4) 11 Saito, I. (19) 308 Saito, K. (5) 33; (20) 18 Saito, T. (3) 279; (16) 18; (21) 57 Saito, Y. (19) 150 Saitoh, T. (3) 138; (4) 41 Sakagami, M. (4) 111; (5) 16; (6) 13 Sakagami, Y. (3) 124 Sakaguchi, K. (11) 24 Sakai, R. (22) 41 Sakai, Y. (3) 180; (9) 73 Sakairi, N. (3) 139; (4) 114 Sakakibara, T. (4) 67; (13) 12; (14) 35; (20) 97 Sakamoto, H. (4) 65 Sakamoto, I. (3) 162; (6) 1; (18) 3 Sakashita, S. (22) 68 Sakata, S. (19) 82, 112 Saksena, A.K. (21) 82 Sakthivel, K. (9) 33 Sakuma, H. (3) 104 Sakuno, T. (3) 204; (7) 16 Sakurai, M. (3) 104 Sala, L.F. (17) 25; (18) 7 Salameh, B.A.B. (10) 47; (19) 21 Salanski, P. (6) 5 Salari, B.S.F. (22) 3 Saleem, R. (3) 108 Saliba, C. (7) 39 Salisbury, S.A. (19) 39 Salisova, M. (4) 206 Sallam, M.A.E. (10) 103; (19) 129 Salter, M.M. (3) 88 Salunkhe, M.M. (19) 257; (20) 77 Salvatore, R.N. (7) 1 Samadi, M. (22) 34 Samoshin, V.V. (3) 318 Samuelsson, B. (16) 8,9 Sanchez, A. (10) 4 Sanchez, S. (1) 18; (4) 100,133 Siinchez-Contreras, S. (7) 58 Sanchez-Vaquero, E. (4) 199
Sander, J. (3) 100 Sandhu, J.S. (9) 18 Sandstrom, C. (21) 30,31 Sandvoss, M. (4) 166 Saneyoshi, M. (19) 189 San-Fklix, A. (7) 70; (19) 97,98 Sankar, A.R. (9) 14 SanMartin, R. (3) 266 Sano, K. (16) 23 Sano, T. (22) 68 Sansonetti, P.J. (3) 149; (4) 47, 145 Santaella, C. (3) 93; (7) 64 Santamaria, F. (19) 232 Santana, L. (19) 149 Santoro, M.I. (18) 7 Santos, H. (14) 17 Santos, M. (18) 76 Santos-Garcia, M. (2) 1; (22) 83 Santoyo-Gonzklez, F. (3) 208, 219; (4) 199,216; (21) 53 Sanz-Tejedor, M.A. (2) 1; (18) 76; (22) 83 Saotome, C. (9) 43; (18) 50,94 Sari, N. (21) 63 Sarkar, A.K. (20) 91 Sarkar, S.K. (3) 32 Sarli, V.C. (22) 63 Sarma, J.A.R.P. (3) 323 Sarre, O.Z. (21) 82 Sartilo-Piscil, F. (19) 50 Sartorelli, A.C. (19) 277,278 Sasaki, M. (22) 41,49 Sasaki, T. (16) 30; (19) 152; (20) 132 Sashiwa, M. (4) 33 Sasmor, H. (19) 224 Sassa, T. (3) 120 Sata, N. (7) 59 Satake, M. (3) 165 Sato, H. (4) 67; (20)97 Sato, N. (16) 20 Sato, R. (5) 1; (20) 110 Sato, S. (3) 279,288,297 Sato, T. (3) 104; (20) 96 Sato, Y. (19) 77 Satoh, T. (9) 19; (16) 7 Satomi, S. (3) 165 Satou, K. (19) 244 Satti, N.K. (3) 294 Sattler, I. (7) 40; (18) 159 Satyamurthi, N. (12) 16 Satyanarayana, J. (4) 69 Saubern, S. (3) 128 Sauerbrei, B. (4) 68; (20) 48 Saul, R. (22) 78 Savarino, P. (10) 19 Savy, P. (4) 87; (7) 62; (18) 46 Sawada, M. (5) 28; (21) 83 Sawada, N. (19) 47 Sawai, H. (19) 77
Sawai, Y. (3) 62,63; (8) 23 Saxena, R. (3) 153 Scaife, W. (20) 129 Scarafoni, A. (19) 291 Schiifer,A. (19) 204 Schafer, T. (19) 310 Schaller, C. (22) 67 Schanzer, J.M. (19) 48,49 Scharwachter, K. (4) 196 Schaub, C. (18) 173 Scheeren, H.W.Q. (7) 6 Scheffler, G. (3) 23 Scheinmann, F. (3) 112, 113; (20) 65 Schell, P. (10) 69 Schenkman, S. (20) 47 Scherman, D. (5) 24; (18) 12 Schiesser,C.H. (11) 37; (18) 5; (19) 307 Schieweck, F. (2) 27; (18) 72 Schiilein, M. (20) 52 Schinazi, R.F. (14) 48; (19) 3,59, 107,279,296 Schlemminger, I. (10) 105 Schleyer,A. (3) 315 Schlienger,N. (19) 185 Schmid, R.D. (7) 29; (20) 71 Schmid, W. (11) 29 Schmidt, A. (21) 27 Schmidt, D. (4) 68; (20) 48,49 Schmidt, M. (3) 75 Schmidt, R.R. (1) 15; (3) 4,23, 37,89,200,310,316; (4) 7, 79,92,109, 126,155, 169; (7) 15; (9) 24, 53; (10) 9; (14) 54; (16) 34; (18) 67, 173; (19) 73,205 Schmitt-Kopplin, P. (21) 122 Schnaar, R.L. (1) 13 Schneider, M.P. (2) 2 Schneller, S.W. (19) 138, 139 Schoefisch,M.H. (1) 14 Schoetzau, T. (19) 12, 102 Schoevaart, R. (20) 101 Schols, H.A. (20) 29 Scholte, A.A. (10) 20 Schonberger, A. (1) 14 Schramm, V.L. (18) 64; (19) 132 Schreiber, A.L. (6) 6; (7) 75 Schuberth, I. (3) 169 Schuhr, C.A. (19) 212; (20) 95 Schulein, M. (4) 31 Schultz, J.E. (16) 54 Schultz, M. (4) 13; (10) 28 Schultz, R.G. (19) 65 Schulz, J. (18) 172 Schulze, 0.(11) 20,36; (19) 88 Schwaiger, M. (3) 257 Schwartz, J. (3) 244; (13) 2 Schwarzer, K. (19) 67 Schwientek, T. (4) 191
Carbohydrate Chemistry
390 Schwogler, A. (10) 5 Schworer, R. (16) 34; (19) 205 Sciammetta, N. (14) 45; (17) 10; (19) 194 Scigelova, M. (4) 27; (20) 17,41, 47 Scott, A.I. (19) 255,256 Scott, L.G. (20) 93 Scott, R.W. (19) 8 Sebastian, R.-M. (3) 78 Sebesta, R. (4) 206 Secrist, J.A., I11 (19) 35,41, 81 Sedmera, P. (20) 64, 135 Seeberger,P.H. (1) 4; (3) 99, 156, 157; (4) 12,39; (10) 69 Seela, F. (19) 202 Seepersaud, M. (18) 100; (22) 4 Segawa, K. (4) 157 Sehgelmeble, F.W. (3) 131 Seifert, J. (4) 183, 184; (20) 53 Seifert, W. (19) 240 Seio, K. (19) 152, 180,219-221 Sekiguchi, M. (19) 117 Sekine, M. (19) 152, 180,181, 2 19-221 Sekiya, M. (4) 52 Sekiyama, T. (19) 295 Sekura, R. (18) 152 Seley, K.L. (19) 138, 139 Selleseth, D.W. (18) 19; (19) 42, 271 Selvakumar, N. (4) 121 Seman, M. (19) 101 Semple, J.E. (22) 79 Senba, Y. (3) 212 Sengupta, P. (4) 78 Sentyureva, S.L. (19) 202 Serafinowski, P.J. (19) 94 Seranni, A.S. (21) 5 Sergey, S.P. (3) 45 Sergueev, D.S. (19) 229 Sergueeva, Z.A. (19) 229 Seri, K.4. (2) 43 Serianni, A.S. (21) 19 Serrano, J.A. (22) 43 Serwecinska, L. (3) 47 Seta, A. (14) 35 Sethi, A. (21) 69 Seto, H. (10) 77; (14) 5-7; (19) 211; (20) 139, 140 Seto, N.O.L. (4) 49; (20) 58 Setoguchi,M. (22) 9 Severino, E.A. (18) 74 Severn, W.B. (18) 31 Seward, C.M.P.(3) 7 Sforza, S. (4) 210 Shabalin, K.A. (10) 50, 51 Shaban, M.A.E. (10) 87 Shah, K. (19) 10 Shailaja, S. (22) 22 Shalamay, A.S. (10) 6; (19) 53
Sharma, G.V.M.(2) 35; (3) 332, 338; (5) 12 Sharma, P.K. (14) 11; (19) 95 Shashidhar, M.S. (18) 113 Shashkov, AS. (4) 75, 128; (21) 35 Shaw, B.R. (19) 213,229 Shaw, C.D. (7) 22; (16) 22 Shaw, D. (18) 55 Shaw, R.B. (19) 192 Sheinmann, F. (7) 30 Sheldon, R.A. (20) 101 Shen, X. (3) 254; (16) 19 Shen, Y.-M. (4) 131 Sheppard, T.L. (7) 53 Sherman, A.A. (4) 128 Shi, Y. (22) 89 Shi, Z. (19) 164 Shibaev, V.N. (7) 47 Shibano, M. (18) 83,93 Shibasaki, M. (22) 101 Shibata, M. (19) 303 Shibuya, I. (10) 40 Shigemasa, Y. (4) 33 Shigemori, H. (7) 59 Shigeta, S. (19) 112 Shih, T.L. (16) 33; (20) 80 Shimada, I. (19) 244 Shimada, S. (4) 52 Shimaoka, M. (19) 175 Shimazu, T. (4) 52 Shimizu, M. (10) 40; (16) 36 Shimizu, N. (4) 97 Shimizu, T. (9) 72; (21) 71; (22) 71 Shimma, N. (19) 47 Shimoaka, M. (20) 133 Shimono, S. (3) 252 Shin, C.-G. (7) 14; (18) 171 Shin, D.S. (19) 29 Shin, H.K. (3) 60; (20) 23 Shin, I. (3) 94; (10) 31 Shindo, K. (3) 127; (9) 1; (14) 20 Shindo, M. (13) 12 Shindoh, S. (19) 119 Shing, T.K.M.(18) 174 Shinkai, S. (3) 95; (6) 18; (21) 89, 97 Shinoda, K. (4) 125; (7) 63 Shinozuka, K. (19) 225 Shinya, K. (10) 77 Shionoyia, M. (3) 333,334 Shiozaki, M. (3) 181,182; (7) 52 Shipitsyn,A.V. (19) 233 Shipkova, P.A. (21) 82 Shipova, E.V. (9) 57 Shirahama, H. (18) 104 Shirai, R. (18) 132 Shirakami, S. (7) 76; (17) 15; (22) 86 Shirato. M. (19) 235
Shireman, B.T. (18) 108 Shiro, M. (7) 78; (18) 156 Shirokova, E.A. (19) 186,233 Shitara, E. (9) 19; (10) 36,37,39; (16) 7 Shizuma, M. (3) 222,223; (5) 28; (20) 31, 39; (21) 83 Shoda, S.-I. (4) 28, 30; (20) 4, 14 Shoham, Y. (21) 27 Shohda, K. (19) 220,221 Shokat, K.M. (19) 10 Shortnacy-Fowler,A.T. (19) 35, 81 Shreeve, J.M. (8) 18; (14) 12 Shum, K. (20) 112 Shutalev,A.D. (19) 28 Shuto, S. (3) 150,259,260,307, 308; (18) 29; (19) 75,91,92, 110,151,234,235; (20) 122 Shvets, V.I. (19) 266 Sickles, B.R. (19) 137 Siddiqui, M.A. (19) 34, 179 Sidduri, A. (19) 72 Sidler, D.R. (21) 72 Siemsen, P. (3) 249; (4) 34 Sifferlen, T. (18) 77 Signorella,R. (18) 7 Signorella, S. (17) 25 Silva, D.J.(3) 48; (9) 12; (19) 153 Silva, M. (14) 17 Silverberg, L.J. (1) 11 Simeoni, L.A. (3) 200 Simicic, L. (7) 17 imo, 0.(10) 104 Simon, A. (19) 282 Simonato, L. (4) 212 Simonet, A.M. (3) 216 Simons, C. (10) 97 Simpson, J. (4) 60 Sims, I.M. (7) 2 Sinay, P. (3) 33,337; (4) 86, 171, 197; (13) 19; (18) 145-147, 181 Sineriz, F. (7) 19 Singh, G. (3) 19, 69, 193; (18) 157 Singh, J. (6) 10; (19) 164 Singh, J.P. (2) 41 Singh, L. (4) 162 Singh, M.P. (2) 41 Singh, R. (3) 294 Singh, R.P. (8) 18; (14) 12 Singh, S. (4) 27; (20) 17,41,47 Singh, S.K. (19) 114, 116 Singh, V.K. (22) 29 Sinnott, M.L. (11) 22; (20) 84 Sinou, D. (3) 236,245; (10) 13; (11) 32; (13) 10 Siren, H. (21) 103 Sjolin, P. (3) 215 Skaanderun P.R. 13) 283: (14)
Author Index 31 Skalsounis, A.-L. (8) 24 Skaltsounis, A.-L. (9) 78 Skelton, B.W. (11) 14 Sklenar, V. (21) 6 Skora, S. (2) 17; (13) 18,24,29; (22) 11, 12,72 Skorupa, E. (18) 17 Skrydstrup, T. (3) 316; (4) 9 0 (13) 3 Slimestad, R. (7) 36 Slivkin, A.I. (7) 13 Slough, G.A. (21) 72 Smiatacz, Z. (3) 47,230; (10) 59, 71-73 Smiataczowa, K. (21) 87 Smidel, A.F. (3) 129 Smith, A.B. (3) 224 Smith, C. (3) 267 Smith, C.L. (19) 39 Smith, D.I. (3) 87 Smith, G.R. (3) 35; (9) 29; (14) 14,27 Smith, M. (3) 38 Smith, M.D. (10) 63 Smith, M.E.B. (4) 141; (18) 68; (20) 12, 102 Smith, R.D. (18) 41 Smith, S.O. (5) 4 Smits, H. (14) 42 Smoliakova, I.P. (3) 253,318; (11)26 Snoeck, R. (19) 143 Snyder, B.B. (22) 40 Soares Fontes, A.P. (17) 29 Sobkowski, M. (19) 169 Sochacka, E. (19) 217 Soderberg, E. (3) 85 Soderholm, S. (21) 78 Sofia, M.J. (1)22; (3) 48,49; (4) 10; (6) 14; (9) 12; (19) 153 Soh, B. (3) 320 Slzrhoel, H. (10) 94; (18) 38 Sol, v. (3) 77 Soler, T. (14) 16 Soli, E.D. (21) 72 Solla, F. (12) 9 Solladib, N. (19) 285 Sollogoub, M. (13) 19; (18) 145, 146,181 Somsak, L. (10) 48,49,83 Sondengam, B.L. (3) 130 Song, B.J. (19) 29 Song, H. (19) 263 Song, Q. (19) 265 Sonnino, S. (4) 85; (20) 125; (21) 64 Sorensen, A.M. (19) 218; (21) 111 Sarrensen, M.D. (19) 113, 114 Soto, J. (13) 14
39 1 Sotofte, I. (18) 69 Souza Filho, J.D. (9) 62 Sowinski, P. (18) 17 Spackman, D.G. (9) 38 Spadaro, A. (3) 231 Spaic, S. (19) 125 Spak, S.J. (3) 304 Spangenberg, P. (20)26 Speckman, D.G. (3) 175 Spector, R. (1) 11 Spencer, J.B. (20) 129 Spencer, K.C. (19) 127 Spencer, R.P. (3) 244; (13) 2 Spielvogel,D. (18) 125 Spies, H.S.C. (7) 10; (17) 18 Spinella, A. (14) 1 Spinelli, S.L. (19) 167 Spiro, M. (3) 77 Sprenger, F.K. (18) 51 Springfield, S.A. (11) 31 Srikrishnan, T. (4) 140 Srimosap, C. (20) 21 Srinivasu, P. (9) 14 Srivastav, S. (21) 69 Srivastav, S.S. (3) 153; (21) 69 Stachulski, A.V. (3) 112; (7) 30; (20) 65 Stankov, S. (19) 125 Stasik, I. (18) 6 Stawinski, J. (19) 169,172,193 St.-Denis, Y. (18) 89 Stead, D.A. (21) 99 Steadman, K.J. (3) 121 Stec, W.J. (19) 31, 170, 171, 184 Steelant, W.F.A. (20) 61 Stefanska, A.L. (19) 165 Steiger, M.A. (19) 167 Steinbach, J. (5) 5; (8) 6 Steinborn, D. (17) 1; (22) 91 Steinecker, V. (4) 61 Steiner, B. (9) 36 Steiner, W. (3) 144; (20)40; (21) 67 Stemp, G. (9) 49; (13) 21 Stephenson, D.E. (20) 64 Stermitz, F.R. (19) 298 Stetsenko, D.A. (19) 250 Steuer, B. (10) 67 Stevens, E.S. (21) 86 Stevensson, B. (21) 68 Stibor, I. (9) 61; (16) 5 Stick, R.V. (11) 14; (20) 20 Stimac, A. (10) 52, 54 Stipetic, M. (7) 17 Stobiecki, M. (21) 79 Stoddart, J.F. (4) 198 Stoddley, R.J. (18) 158 Stoisavljevic,V. (19) 228,240 Storer, M. (10) 41 Stortz, C.A. (21) 52 Stover, M. (22) 77
Strazewski, P. (19) 45 Strecker, G. (4) 142 Strehler, C. (10) 70; (22) 82 Streicher, H. (11) 29 Streith, J. (9) 47;'(10) 70; (18) 77; (22) 82 Strekowski, L. (19) 13, 14 Stroyan, E.P. (21) 86 Stutz, A.E. (8) 13; (10) 62; (13) 1; (18) 31, 51, 53; (20) 134 Su, M. (5) 21 Suarez, E. (2) 37; (3) 299; (5) 34; (10) 17 Suarez, J.Q. (14) 58 Subhas Bose, D. (6) 12 Subhash-Chander, A. (3) 338 Subhasitanont, P. (20) 21 Suchek, S.J. (18) 162 Suda, M. (10) 7 Suda, S. (21) 71 Suda, Y.(3) 180; (9) 73 Suemune, H. (15) 4 Sugahara, N. (4) 200 Sugai, T. (19) 258; (20) 81 Sugawara, F. (11)24 Sugimoto, H. (18) 83,93 Sugimoto, I. (14) 24; (19) 92, 111 Sugimoto, N. (1) 19 Sugimoto, 0.(19) 155 Sugimoto, T. (19) 117 Sugimura, H. (9) 28; (22) 35 Sugimura, M. (19) 126 Sugita, M. (4) 76 Sugiyama, K. (4) 48 Sugiyama, S. (3) 21; (4) 152; (8) 17 Suhaimi, H. (21) 41 Suhara, Y. (4) 15; (22) 8 Suisse, I. (22) 90 Suivasono, S. (4) 26 Sujino, K. (4) 49; (20) 63 Sukeda, M. (19) 92 Sukuki, S. (21) 109 Sumita, Y. (19) 235 Sumiya, M. (16) 30 Summers, J.S. (19) 229 Sun, C. (19) 25 Sun, S. (4) 121 Sun, X.-L. (3) 55; (16) 20,29 Sunada, A. (18) 160, 161;(20) 75,76 Sunazuka, T. (19) 161 Sundarababu, G. (8) 16 Sundaram, A.K. (16) 17; (20) 138 Sunder, K.S. (22) 22 Sundquist, B.G. (4) 144 Suomi, J. (21) 103 Surarit, R. (20) 21 Suresh, C.G. (9) 33 Sureshan, K.M. (18) 113
392 Takahashi, H. (2) 10; (18)98 Takahashi, M. (14) 46; (18) 85, 92, 153, 154; (22) 14,52 Takahashi, S. (5) 28; (7) 72; (11) 24; (19) 264; (21) 83 Takahashi, T. (4) 36 Takai, M. (4) 42; (20) 22; (21) 58 Takai, S. (9) 51; (22) 7 Takai, Y. (5) 28; (21) 83 Takano, R. (9) 51 Takao, K. (22) 6,76 Takatani, M. (4) 138 Takayama, H. (22) 8 Takayanagi, H. (22) 8 Takeda, T. (4)76,97,137; (5) 28; (16) 36; (19) 303; (21) 83 Takehara, T. (4) 52 Takenaka, F. (20) 19 Takenaka, K. (3) 104 Takenouchi, K. (19) 203; (20) 104 Takesue, H. (9)42 Takeuchi, K. (3) 137, 138, 147, 176; (4) 40,41,45 Takeuchi, M. (2) 8,9; (14) 49; (21) 89 Takeuchi, T. (9) 19; (10) 36, 37, 39; (16) 7 Taktakishvili, M. (19) 166 Talser, D.F. (3) 57 Tam, R.C. (19) 11,16 Tamagaki, S. (4) 21 1 Tamaka, K.S.E. (20) 113 Tamaki, H. (3) 61; (21) 92 Tamakoshi, H. (3) 164; (20) 57 Tamamura, H. (22) 27 Tamayo, J. (3) 298; (20) 69 Tamura, H. (22) 9 Tamura, S.Y. (22) 79 Ta, C.D. (4) 50; (20) 28 Tamura, T. (3) 147,176;(4) 45 Tabaczynski, W.A. (4) 165 Tanabe, K. (22) 59 Tachibana, K. (22) 41,49 Tanabe, M. (3) 286,287 Tadano, K. (22) 5,6,76 Tanahashi, E. (4) 124; (16) 31 Tagashira, M. (3) 295; (12) 4 Tanaka, H. (4) 74; (19) 119 Tagaya, H. (3) 20 Tanaka, K. (3) 333,334; (4) 193, Tagliaferri, E.G. (21) 115 194; (16) 23; (20) 24,25 Tagliapietro, S. (4) 195; (21) 101 Tanaka, N. (18) 154; (22) 52 Taguchi, K. (22) 71 Tanaka, S. (10) 3 Taguchi, N. (21) 109 Tanaka, T. (18) 1 Tahir, H. (16) 53 Tandon, P.K. (2) 41 Tahrat, H. (20) 61 Tang, J. (19) 245 Tai, B.-S. (12) 3 Tang, Y.-Q. (18) 159 Taillefumier, C. (3) 264; (18) Tani, S. (3) 189 178; (22) 13 Taniguchi, H. (18) 117 Tajiri, K. (18) 70 Taniguchi, T. (2) 8,9; (14) 49 Takabe, K. (22) 58 Tanimori, S. (20) 78 Takada, G. (2) 15; (20) 127 Tanimoto, T. (4) 192-194;(20) Takada, J. (11) 3 24,25 Takagi, K. (4) 99 Tanticharoen, M. (3) 122 Takagi, M. (14) 5-7; (19) 211; Tao, J. (3) 289 (20) 139, 140 Tao, Y. (4) 121 Takagi,’Y.(3) 72
Suri, K.A. (3) 294 Suri, O.P. (3) 294 Surma, Z. (1) 16 Sutter, J.-P. (17) 27; (18) 14 Suwasono, S. (20) 16 Suwinska, K. (22) 53 Suzuki, H. (1) 17,18; (4) 2-5; (11) 38,39; (12) 6,8; (14) 10, 28 Suzuki, K. (3) 109,205,286, 287,292; (9) 10; (18) 65; (19) 295 Suzuki, M. (22) 50 Suzuki, T. (10) 3 Suzuki, Y. (3) 55,61; (16) 29; (20) 33,34 Svasti, J. (20) 21 Svedrucic, D. (16) 50 Svendruzic, D. (9) 5 Svensson, B. (20) 123; (21) 60 Swank, D.D. (21) 43 Swanson, S. (7) 22; (16)22 Swansson, L. (11) 12 Swayse, E.E. (18) 166 Sweedler, D. (19) 246 Szabovik, G. (4) 89 Szarek, W.A. (1)28; (8) 12,21; (12) 13 Szeja, W. (3) 190; (11) 18 Szewczyk, K. (13) 24; (22) 72 Szilagyi, L. (4) 35,89; (5) 17; (6) 3; (21) 24 Szolcsanyi, P. (18) 58,59 Szpacenko, A. (20) 58 Sztaricskai,F. (19) 74 Szurmai, Z. (10) 58
Carbohydrate Chemistry Tappertzhofen, C. (4) 88 Tarahara, H. (19) 47 Tardella, P.A. (9)41 Tarelli, E. (18) 127 Tarnus, C. (9) 47; (18) 77 Tarui, T. (21) 92 Tarussova, N.B. (19) 186,233 Tatibouet, A. (3) 272; (5) 9; (11) 5; (18)62 Tatsuta, K. (14) 46; (18) 153, 154; (22) 14, 52 Tattersall, P.I. (14) 45; (17) 10; (19) 194 Tauss, A. (8) 13; (10) 62; (20) 134 Tavassoli, B. (3) 266 Taverner, T. (19) 307 Tawaki, H. (20) 33,34 Taylor, C.W. (3) 151,255; (19) 157,159 Techasakul, S. (20) 21 Teijeira, M. (19) 149 Teixeira Cesar, E. (17) 29 Tejero, T. (19) 282-284 Temeriusz, A. (4) 214; (21) 32 Tenilla, T. (19) 57 Tennant-Eyles, R.J. (3) 155 Teo, C.-F. (2) 12; (5) 29 Terada, Y. (21) 54 Terai, T. (7) 32 Teramichi, R. (19) 144 Teran, C. (19) 149 Teranishi, K. (4) 201,202 Teranismi, K. (7) 73 Terauchi, M. (3) 260 Terler, K. (3) 144; (20) 40 Terrade, A. (9) 34; (14)25 Terrai, T. (20) 114 Terunuma, D. (3) 84 Teruya, K. (4) 127 Tessot, N. (14) 52 Tettamanti, G. (20) 125 Tezuka, K. (10) 108 Tezuka, Y. (3) 68 Thelland, A. (10) 75 Thentaranonth, Y. (3) 122 Therisod, M. (18) 60 Thiele, G. (10)98; (14) 57 Thiem, J. (3) 164, 167, 194; (4) 29,68; (19) 204; (20) 35,42, 48,49,57, 130 Thiericke, R.(7) 4 0 (18) 159 Thiery, J.C. (18) 10 Thoithi, G.N. (19) 311 Thoma, G. (4) 117 Thomas, M. (19) 238 Thomas, N.R.(18) 41 Thomassigny, C. (7) 19,20 Thomazeau, C. (16) 40 Thomsen, I.B. (10) 93; (18) 39 Thomson, R.J. (9) 60; (16) 21,24 Thopate, S.R.(2) 14
393
Author Index Thorhauge, J. (2) 6; (16)43 Thornmauge, J. (9) 45 Tian, W. (17) 20; (21) 74,75 Tian, X.B. (19)272 Tian, X.-X. (5) 2 Tidwell, J. (19)9 Tietze, L.F. (3) 169; (4) 88 Tifft, C.J. (1) 11 Tilbrook, D.M.G. (11) 14 Tilekar, J.N. (16) 47; (22) 33 Timmer, M.S.M. (17) 11 Timoshchuk, V.A. (19) 99 Tiwari, K.N. (19) 81 Tjima, N. (19)303 Tjuji, T. (19) 295 Tkachenko, O.V. (19) 202 Tkadlecovh, M. (9) 61; (16) 5 Tobiason, F.L. (21)43 Todeschini, A.R. (20) 118 Todhunter, N.D. (11) 15 Tofani, D. (9) 41 Togo, H. (14) 33 Toida, T. (20) 142 Tokuda, K. (14) 35 Tokuyasu, K. (7) 31; (20) 78,79 Tolbert, T.J. (18) 162; (20) 66,93 Tolborg, J.F. (9) 69 Tolstikov, G.A. (3) 116 Tomino, K. (14) 24; (19) 111 Tomita, F. (5) 33; (20) 18 Tomonaga, F. (3) 104; (4) 52 Tomooka, K. (3) 326; (22) 50 Tona, R. (3) 50; (19) 267 Tonellato, U. (4) 212 Tong, K.-F. (7)7 Tong, L.-H. (4) 200 Toone, E.J. (3) 78,268; (4) 51; (20) 5 Topalov, G. (19) 38 Toppet, S. (18) 47 Tor, Y. (4) 115; (9) 66,67; (18) 167,169 Torii, T. (20) 85 Torizawa, T. (19) 244 Torovic, L. (19) 125 Toshima, K. (3) 2,42, 161; (8) 2; (9) 51 Totani, K. (22) $76 Toth, A. (3) 186 Toth, B. (10)48 Toth, I. (10) 33 Toupet, L. (3) 30 Townsend, L.B. (19) 9, 19,20, 42-44,58 Toyoda, T. (4) 124; (16) 31 Toyoshima, M. (10) 37 Toyota, A. (19) 104 Trevisol, E. (19) 200 Trifonova, A. (19) 4 Trincone, A. (20) 50 Trnka, T. (9) 68
Trombini, C. (10) 80 Trombotto, S. (3) 217; (16) 40 Tronchet, J.M.K. (19) 101 Trost, B.M. (19) 134 Trotter, N.S. (18) 158 Trumakaj, Z. (7) 4 Trusov, S.R. (2) 42 Trynda, A. (21)44 Tsai, C.-H. (2) 11; (16) 12 Tsai, C.-Y. (3) 314; (16) 32 Tsai, F.-Y. (5) 14; (19) 254 Tsai, T.-H. (21) 113 Tsay, S.-C. (19)254 Tseng, P.-H. (3) 83, 172 Tsuchiya, K. (5) 1; (20) 110 Tsuchiya, T. (3) 72; (18) 168 Tsuda, T. (4)65 Tsuhako, M. (7) 42,43 Tsuji, E. (19)22 Tsuji, S. (20) 63 Tsujimoto, M. (7)72; (19) 264 Tsukamoto, D. (18) 83,93 Tu, G. (3) 289; (4) 104 Turek, D. (4) 156 Turks, M. (14) 42 Turnbull, W.B. (3) 239 Turner, D.H. (19) 167 Turner, N.J. (7) 30; (18) 68; (20) 12,65 Tusa, G. (19) 199 Tworowska, I. (19) 195 Tyler, P.C. (18)64; (19) 132; (20) 121 Uchiyama, H. (20) 19 Uchiyama, T. (4) 49, 189; (20) 30 Uda, J. (19) 155 Ueda, K. (3) 3, 118 Ueda, M. (3) 62,63, 118; (7) 59; (8) 23 Uemura, S. (22) 100 Ueno, A. (9) 81 Ueno, Y. (14) 24; (19) 110, 111, 234,235; (20) 122 Ugama, H. (20) 74 Ugarkar, B.G. (19) 48,49 Ughetto-Monfrin, J. (4) 146, 147 Uhrig, R.K. (3) 58 Ulfstedt-Jaekel, K. (21) 68 Ullah, G.M. (11) 1; (19) 84-86 Ullman, A. (3) 140; (11) 17 Ulrich, S.M. (19) 10 Ulug, E.M. (18) 133 Ulven, T. (12) 19 Umadevi, B. (18)49; (21) 7 Umeda, I. (19) 47 Umezawa, K. (4) 157; (19) 150 Umino, T. (19) 287
Unger, F.M. (11) 29 Ungheri, D. (19) 280 Unversagt, C. (4) 178, 184; (20) 53 Uong, T.H. (22) 79 Upreti, M. (4) 106 Ura, M. (19)47 Urashima, T. (16) 18; (21) 57 Urata, H. (19) 144 Urbanczyk-Lipowska, Z. (21) 34; (22) 53 Uriarte, E. (19) 149 Uriel, S. (10) 81 Usenko, L.S. (19) 53 Usov, A.I. (4)75 Usova, E. (21) 38 Ustuzhanina, N.E. (4)75 Usuda, Y. (19) 175; (20) 133 Usui, K. (20) 37 Usui, T. (3) 166 Utagawa, T. (19) 175; (20) 133 Utzmann, C.M. (9) 6 Uyeda, M. (3) 125 Vacek, M. (3) 65; (20) 27 Vaidyanathan, R. (7) 69 Vaino, A.R. (1) 28; (8) 21 Valdez, C.A. (2) 20; (19) 121 Valentijn, A.R.P.M. (2) 36; (3) 151 Valiry, J.-M. (3) 261,277; (17) 3; (19) 262 Valivety, R. (2) 49,50; (3) 28; (20) 46 Valle, N. (14) 39,40 Valsborg, J.S. (18) 73 Valverde, S. (3) 6; (4) 73 Van Aerschot, A. (19) 276,311 Van Bekkum, H. (2) 39; (18) 8 van Boom, J.H. (2) 3,36; (3) 151, 152; (9) 11; (17) 11; (19) 36, 160; (20) 11; (21) 65 Van Calenbergh, S. (19) 63 van Casteren, W.H.M. (20) 29 van Dam, G.J. (20) 43 van Delft, F.L. (3) 132; (4) 2; (11) 40; (12) 7; (14) 28 van den Brock, L.A.M. (20) 29 van der Broeck, H. (21) 102 van der Eijinden, D. (20) 43 van der Eycken, E. (18) 150 van der Eycken, J. (18) 150 van der Gaast, S.J. (3) 98 van der Marel, G.A. (2) 36; (3) 151, 152; (9) 11; (17) 11; (19) 160; (21) 65 van der Merwe, M.J. (17) 18 van der Padt, A. (3) 29 Vandersteen, A.M. (19) 265 Van Die, I. (20) 43
394 van Draanen, N. (19) 9 van Halbeek, H. (1) 12; (20) 118 Vankar, Y.D. (3) 282; (14) 55 Vankayalapati, H. (3) 19,69, 193 van Kuik, J.A. (4) 81 van Rantwijk, F. (20) 101 van Remoortere, A. (20) 43 Van Rooijen, J.J.M. (21) 62 Van Shepdael, A. (19) 3 11 van Smaalen, S. (21) 93 Van Vranken, D.L. (3) 191; (10) 8 Varela, 0.(9) 76; (10) 91; (16) 16; (17) 28 Vargiu, L. (19) 40 Varki, A. (1) 12; (20) 118 Vasella, A. (2) 34; (3) 246,278; (10) 74,96, 109-112;(17) 14; (18) 91; (19) 285,286, 288,289; (21) 28,29 Vasquez, G. (19) 249 Vega, J.A. (9) 25; (13) 6 Vega-Perez, J.M. (3) 46 Velazquez, S. (7) 70; (19) 97,98 Vemishetti, P. (1) 11 Veno, A. (3) 107; (18) 163 Vepsdainen, J. (19) 57 Vercellotti, J.R. (2) 46 Verdoorn, G.H. (18) 45 Vergoten, G. (21) 43 Verlinde, C.L.M.J. (10) 26 Vermeer, H.J. (3) 179; (4) 81 Vertuani, S. (16) 51; (19) 40 Vetere, A. (20) 38 Viala, J. (22) 2 Viani, F. (19) 56 Vic, G. (4) 27; (20) 17 Vicat, P. (14) 52 Vichier-Guerre, S. (19) 232 Victorova, L.S. (19) 202 Vidal, J.-P. (22) 1,2 Vidal, S. (2) 19; (17) 5 Vidal-Cros, A. (10) 75 Vidil, C. (2) 19; (17) 5 Vieceli, 0.(19) 283 Vierling, P. (3) 93; (7) 64 Vigh, G. (4) 205; (7) 60 Vignon, M.R. (16) 41 Vijayasaradhi, S. (6) 10 Vilarrasa, J. (19) 68 Villa, P. (6) 9; (7) 56; (9) 4,35; (11)23; (14) 26; (22) 88 Villani, F.J., Jr. (3) 35; (14) 14 Vincent, S.P. (3) 315; (4) 182; (19) 207; (20) 60,90 Vincken, J.-P. (20) 29 Viornery, L. (7) 39 Vipond, D.H. (1) 11 Virgona, C. (18) 51 Viscardi, G. (10) 19
Carbohydrate Chemistry Wang, G. (19) 17,228,297; (22) 19 Wang, G.Y. (19) 16 Wang, H. (2) 48 Wang, H.-Y. (4) 18 Wang, J. (2) 48; (19) 143 Wang, L.X. (20) 96 Wang, P.G. (20) 100 Wang, Q. (3) 262 Wang, R.W. (18) 37 Wang, S. (18) 143 Wang, T. (19) 174 Wang, W. (13) 19; (18) 181 Wang, Y. (10) 69 Wang, Z . (17) 20; (19) 33; (21) 75 Wang, Z.-G. (9) 26; (10) 30 Wang, Z.-X. (3) 335, 336 Wanner, M.J. (19) 15 Ward, C.J. (21) 88 Warr, S.R. (19) 165 Warren, C.D. (21) 61 Warren, R.A.J. (20) 51 Warwel, M. (16) 26 Watanabe, G. (22) 6 Watanabe, H. (14) 6,7; (20) 139, 140; (22) 80 Watanabe, M. (7)42 Watanabe, N. (3) 117; (4) 48; (21) 54 Watanabe, T. (20) 78 Watanabe, Y. (3) 117; (18) 135 Wataya, Y. (7) 76 Watson, A.A. (18) 84-86,92 Watson, J.N. (10) 20 Watt, D.K. (4) 60 Watt, G.M. (7) 44 Watterson, M.P. (10) 63 Waud, W.R. (19) 81 Wachtmeister, J. (16) 9 Wauk, S.F. (2) 20 Wada, S. (4) 48; (20) 74 Wada, T. (4) 200,209; (19) 152, Wawer, I. (21) 32 Wazynska, M. (4) 214 180,181,219-221 Weber, H. (21) 67 Wada, Y. (3) 63; (8) 23 Weber, K.T. (3) 256 Wadouachi, A. (2) 22; (7) 66; Wegner, C. (4) 57 (15) 2 Wegner, R. (9) 70 Wagle, D.R. (22) 54 Wehner, V. (10) 67 Wagner, B. (4) 110; (20) 62 Wei, Y. (19) 19; (21) 110 Wagner, C.R. (19) 183,263 Weimar, T. (20) 123; (21) 26,60 Wakabayashi, M. (4) 127 Weingart, R. (3) 37 Wakarchuk, W.W. (4) 49,93; Weinhold, E. (11) 21; (19) 87 (20) 89 Wellner, E. (3) 92 Wakayama, T. (19) 189 Wakiuchi, N. (3) 61; (20) 33, 34; Wen, X. (19) 54 Wendeborn, S. ( 5 ) 32; (9) 3; (11) (21) 92 28 Walczak, K. (19) 268 Waldmann, H. (3) 100; (20) 141 Weng, M. (10) 92 Weng, S. (17) 20; (21) 75 Walsh, K.E. (3) 266 Weng, S.-F. (21) 74 Walter, A. (3) 276 Wengel, J. (19) 5, 109,113-116, Walter, D.S. (3) 266 118 Wandzik, I. (3) 190 Wenger, W. (2) 34; (17) 14 Wang, C.-C. (2) 14 Wenska, M. (19) 169,193 Wang, D. (19) 25
Viscontin, C. (19) 265 Vishnyakov, A. (21) 12 Vishwakarma, R.A. (4) 106; (18) 111 Vismara, E. (21)90 Viso, A. (19) 78 Vittori, S. (19) 44 Viuf, C. (5) 19; (6) 2 Vivien, V. (18) 97 Vliegenthart, J.F.G. (3) 179;(4) 81; (7) 26; (21) 62 Vogel, C. (3) 145; (4) 44,63; (16) 45,46 Vogel, G. (18) 129 Vogel, J. (4) 109 Vogel, P. (3) 305; (10) 61; (14) 56; (18) 88,96; (22) 67 Vogel, R. (3) 31 1 Vohler, M. (21) 72 Voitsek, P. (3) 210; (14) 47 Volc, J. (20) 135 von Frijtag Drabbe Kunzel, J.K. (19) 15 Vongvanich, N. (3) 122 von Itzstein, M. (3) 226,241; (9) 60; (11) 16; (16) 21,24,28; (20) 117 Von Philipsborn, W. (21) 72 Voragen, A.G.J. (20) 29 Vosejpka, L.J.S. (21) 72 Voss, G. (16) 52; (21) 93 Voss, J. (11) 2,20, 36; (19) 83, 88 Votavova, H. (9) 15 Voznyi, Ya.V. (3) 142; (20) 144 Vulfson, E.N. (3) 27; (20) 1
395
Author Index Wenzl, I. (11) 29 Wenzl, P. (18) 170 Wernicke, A. (16) 4 Wester, H.-J. (3) 257 Westermann, B. (3) 276 Weychert, M. (21) 32 Whitcomb, I.W.A. (3) 51 Whitcomb, J.W.A. (10) 79 White, A.H. (11) 14 White, J.D. (22) 61 Whitfield, D.M. (4) 77,93; (20)
Wojczewski, C. (19) 67,79 Wojnowski, W. (10) 18 Wolff, M. (3) 262 Wong, C.-H. (1) 6,7; (3) 55,66,
314, 315; (4) 9,22, 141, 158, 180-182; (7) 53; (10) 107; (16) 29, 32; (18) 50,94, 162; (19) 207; (20) 3,7, 8, 54, 59, 60,66,88,90, 102; (22) 62 WOO,M.-C. (3) 107; (9) 81; (18) 163 Woodard, R.W. (16) 17; (20) 89 138 Wicki, J. (3) 43 Woodley, J.M. (16) 15; (20) 87 Widmalm, G. (21) 12,40,68 Woods, A.S. (4) 217 Wiebe, L.I. (3) 335, 336 Woodward, S. (11) 30; (22) 98 Wieczorek, M. (19) 31 Worden, S. (19) 120 Wiemer, A.J. (19) 190 Worden, T.V. (3) 115 Wiemer, D.F. (19) 168,190 Wormald, M.R. (3) 67 Wiesner, J.B. (19) 48,49 Wotring, L.L. (19) 44 Wiessler, M. (3) 58 Wightman, R.H. (19) 27; (22) 81 Wozniak, L.A. (19) 170,171 Wrightman, R.H. (18) 97 Wijkhuisen, A. (4) 207 Wilczewska, A. (7) 74; (18) 118; Wrinkler, T. (20) 62 (19) 260 Wrodnigg, T.M. (13) 1; (18) 31, 51 Wilde, H. (10) 14 Willett, J.L. (4) 190; (21) 10, 11 Wu, H. (18) 175 Williams, D.H. (20) 129 Wu, J. (17) 20; (21) 75 Williams, D.K. (19) 8 WU,J.-G. (21) 74 Williams, D.L.H. (16) 48 Wu, S.H.(4) 18; (16) 33; (20) 80 Williams, H.J. (19) 255, 256 Wu, W.D. (19) 275 Williams, L.J. (4) 150, 160; (7) Wu, X. (4) 82, 103; (19) 253 WU,X.-J. (19) 270 27 Wu, Y. (3) 254; (16) 19,25 Williams, P.A.M. (17) 23 WU,Y.-J. (4) 121 Williams, R.M. (19) 71 WU,Y.-L. (3) 254; (16) 19,25 Williams, S.J. (3) 43; (8) 3; (11) Wungsintaweekul,J. (19) 212; 14; (20) 13 (20) 95 Wilson, J.C. (9) 60; (16) 24,28; (20) 117 Wunsch, G. (4) 166 Wimmer, N. (3) 200 Wunschel, M. (21) 93 Wymer, N. (20) 5 Wimmer, Z. (3) 65; (20) 27 Winchester, B.G. (1) 10; (21) 84 Winckler, M. (19) 24 Winkler, F.K. (19) 251 Xia, J. (4) 66, 139, 140, 163, 164; Winkler, M. (10) 88 ( 5 ) 18 Winkler, T. (4) 110 Xiao, D. (3) 203 Winter, J.J.G.(9) 49; (13) 21 Xie, F. (3) 52 Xie, J. (3) 261,277; (17) 3; (19) Winterfeld, G.A. (9) 24; (10) 9; 262 (19) 73 Wirsching, J. (11) 36; (19) 83,88 Xie, Y.-Y. (10) 16 Wirtz, C. (3) 133 Xu, W. (11) 31 Wisniewski, A. (10) 18; (18) 17; Xu, X. (3) 289 Xu, Y. (17) 2 0 (18) 66; (21) 75 (21) 44 Witczak, J.W. (14) 29 x u , Y.-z. (21) 74 Witczak, J.Z. (3) 237; (11) 33 Xuereb, H. (4) 123 Withers, S.G. (1) 9; (3) 43,213; (4) 24; (8) 3; (18) 51; (20) 13, 15,20, 51, 105, 112 Yadav, J.S. (5) 13, 15; (13) 15 Witt, U.G. (16) 54 Yago, K. (3) 104; (4) 52 Wittmann, V. (3) 99; (4) 180; Yahara, S. (12) 3 (20) 54 Yahiro, Y. (3) 259,260; (18) 29 Wnuk, S.F. (19) 121 Yalowitz, J.A. (19) 124
Yamada, H. (3) 40,72; (4) 97; (5) 28; (16) 36; (21) 83
Yamada, I. (10) 3 Yamada, K. (4) 129; (10) 3; (19) 82,225
Yamada, R. (19) 161 Yamada, T. (4) 201; (21) 120 Yamagata, S. (20) 96 Yamagata, T. (20) 96 Yamaguchi, H. (3) 286,287 Yamaguchi, K. (14) 33 Yamaguchi, S. (18) 57 Yamamoto, A. (4) 127 Yamamoto, H. (3) 326 Yamamoto, K. (4) 200 Yamamoto, M. (18) 84; (21) 89 Yamamoto, T. (3) 61; (20) 33, 34
Yamamura, S. (3) 3,62,63,118;
(7) 59; (8) 23; (19) 150 Y amana, K. (19) 64 Yamano, Y. (3) 117 Yamase, H. (9) 9; (20) 103 Yamashita, K. (3) 154; (4) 43; (7) 46 Yamashita, Y. (7) 76 Yamatoya, Y. (19) 147 Yamauchi, M. (22) 73 Yamauchi, S. (22) 38, 39 Yamauchi, T. (18) 124 Yamazaki, 0.(14) 33 Yamazaki, T. (11) 24; (14) 60 Yan, D.-Q. (4) 204 Yan, F. (4) 93 Yan, Y. (7) 29; (20) 71 Yanagi, T. (19) 181 Yanagisawa, Y. (22) 5 Yananoi, T. (3) 154; (4) 43; (7) 46 Yanase, M. (3) 221 Yang, B.-H. (19) 270 Yang, D.-Y. (21) 113 Yang, G. (4) 168 Yang, H.O. (20) 142 Yang, J. (3) 57; (5) 9 Yang, L. (17) 20; (21) 75 Yang, L.-L. (21) 113 Yang, L.-M. (21) 74 Yang, M.S. (18) 40 Yang, W.-B. (2) 11, 12; (5) 29; (16) 12 Yang, W.K. (18) 15; (22) 96,97 Yang, X. (2) 20; (19) 121 Yang, X.-B. (19) 3 1 Yang, Y.-K. (3) 207; (14) 19 Yang, Y.-Y. (2) 12; (5) 29 Yang, Z. (1) 17; (3) 24; (5) 21 Yano, S. (16) 30 Yao, T.-W. (21) 105 Yarovenko, V.N. (19) 123 Yasuda, M. (5) 1; (20) 110
Carbohydrate Chemistry Yasui, Y. (3) 287 Ye, X.-S.(4) 9 Ye, Y.-P. (4) 131 Yeung, B.K.S. (4) 56; (9) 54 Yin, H.-B. (3) 293 Yli-Kauhaluoma, J.T. (7) 55 Yoda, H. (22) 58, 59 Yokomizo, K. (3) 125 Yokoyama, H. (18) 57 Yokoyama, M. (8) 1; (14) 33; (19) 80 Yoneda, F. (16) 30 Yonehara, K. (22) 100 Yonemitsu, 0.(22) 73 Yoo, J.S. (21) 80 Yoo, K.S. (4) 208 Yoon, D. (19) 140 Yoon, J.H. (3) 171; (20) 36 Yoshida, T. (3) 104; (19) 216 Yoshikawa, M. (3) 119 Yoshimoto, T. (14)46; (22) 14 Yoshimura, K. (19) 112 Yoshimura, Y. (19) 82 Yoshinari, T. (10) 7 Yoshino, R.(3) 166; (20) 37 Yoshizaki, H. (3) 180; (9) 73 Yosmida, T. (7) 76 You, c.-c. (4) 209 Youn, J. (16) 27 Young, V.G. (2) 4 Yu, BT(1) 17; (3) 24. 203,206; (4) 82, 103; (16) 42 Yu, G. (20) 142 Yu, H. (4) 103 Yu, H.N. (3) 41; (12) 17 Yu, J. (3) 128 Yu, w. ( 5 ) 21 Yu, Y. (19) 93 Yuan, D.-Q. (4) 203 Yuasa, H. (11) 3; (18) 152 Yue, Y. (2) 48 Yui, T. (21) 59 Yukita, A. (19) 189 Yumoto, T. (19) 144 Yuo, T. (4) 72 Yus, M. (14) 13, 16 '
Zaborowski, A. (3) 47 Zabriskie, T.M. (19) 156 Zacharie, B. (19) 28 1 Zahner, H. (7) 40 Zakirova, N.F. (19) 186 Zamfir, A. (21) 119 Zamojski, A. (2) 18 Zanardi, F. (18) 102; (19) 291 Zannetti, M.T. (20) 9 Zaragoza, R.J. (10) 81 Zard, S.Z. (7) 74; (18) 118;(19) 260 Zarevucka, M. (3) 65; (20) 27 Zatonskii, G.V. (4) 75 Zatorski, A. (4) 150 Zatsepin, T.S. (19) 250 Zavacka, E. (9) 30 Zavgorodny, S.G.(19) 266 Zavodnik, V.E. (19) 28 Zawisza, A. (3) 236; (11) 32 Zech, G. (10) 34 Zechel, D.L. (1)9; (20) 51, 105 Zeeck, E. (7) 40 Zemlicka, J. (19) 293,294 Zen, S . (3) 104; (4) 52 Zeng, S. (21) 105 Zeng, X. (3) 166; (20) 37 Zenk, M.H. (19)212; (20) 95 Zenke, G. (3) 90 Zerbe, 0.(21) 72 Zessin, J. ( 5 ) 5 Zhang, G . (19) 25 Zhang, H. (19) 269 Zhang, J. (19) 25 Zhang, K. (21) 8 Zhang, L. (19) 269 Zhang, L.H. (19) 272,273,275 Zhang, M. (4) 154; (19)269 Zhang, P. (3) 41; (9) 58; (12) 17 Zhang, P.-Z. (19) 265 Zhang, Q. (19) 156 Zhang, R. (4) 104 Zhang, R.-S. (4) 131 Zhang, W. (20) 100 Zhang, X. (3) 199; (9) 26; (10) 30; (19) 93
Zhang, X.-F.(4) 150 Zhang, Y. (4) 171; (9) 58; (13) 19; (18) 9,181 Zhang, Z. (10) 26 Zhao, D. (10) 38 Zhao, J. (7) 3 Zhao, L. (9) 9; (20) 103 Zhao, Y. (3) 289; (4) 104; (11)22; (17) 20; (20) 84; (21) 75 Zhao, Y.-F. (7) 50; (19) 61, 178 Zheng, B.-Z. (22) 73 Zheng, Q.-T. (3) 207; (14) 19; (19) 275 Zheng, S.-L. (11)37; (18) 5 Zhong, Y.-L. (9) 25; (13) 6 Zhou, R.-L. (3) 170 Zhou, W. (19) 177 Zhou, Y.-S. (19) 61, 178 Zhu, A. (20) 112 Zhu, J. (10) 21 Zhu, L.L. (18) 37 Zhu, T. (3) 25,59; (4) 46,159 Zhu, W. (18) 112 Zhu, X. (16) 42 Zhu, X.F. (19) 133,255,256 Zhu, X.-M. (3) 206 Zhu, Y. (4) 38,91, 102, 176; (21) 5 Zhu, Y.-H. (3) 305 Zhu, Z. (19) 20 Zhuang, A. (9) 45 Zhuo, K. (2) 48 Ziang, J.-Z. (12) 3 Ziegler, H. (4) 105 Ziegler, T. (3) 5, 101, 158, 159, 265; (4)94; (10) 27 Zielinski, M. (19) 276 Zimmerman, C.L. (19) 263 Zimmermann, W. (20) 70 Zollo, F. (4) 143 Zou, J. (1) 19 Zou, K. (4) 104 Zou, R. (19) 43 Zuercher, W.J. (19) 135 Zuilhof, H. (3) 29; (20) 115 Zurcher, G . (19) 25 1